Conférences 2016

Les Conférences : Année 2016

Invitation : Derrick Robinson – UMR CNRS 5234

Mercredi 14 décembre à 11 h

Salle de conférences de la Plateforme Génomique Fonctionnelle, site de Carreire zone sud, université de Bordeaux

Samuel Dean
University Of Oxford

“Composition, function and dynamics of the trypanosome flagellum transition zone”

Cilia are highly conserved organelles present in most eukaryotic cell types. The transition zone (TZ) is a ciliary subdomain that acts as a “gate” to control the composition of the cilium. The importance of the TZ is reflected in the many human diseases (termed ciliopathies) that are caused by mutations in TZ complexes. Here, we use a new proteomics technique to find new components of the African trypanosome TZ. We leverage the extraordinary tractability of this system to investigate TZ proteins, localizing them to distinct subdomains within the TZ, and demonstrating their essential roles in building cilia. We show that while orthologs of some ciliopathy complexes show long-term association with the TZ, others are highly dynamic.

 

Invitation : Mélanie Bonhivers – UMR CNRS 5234

 

Vendredi 9 décembre à 11 h


Salle de conférences RMSB, site de Carreire zone Nord, université de Bordeaux

Sue Vaughan
Senior Lecturer in Cell and Molecular Biology
Department of Biological and Medical Sciences – Faculty of Health and Life Sciences
Oxford Brooke University

“Using 3D microscopy to study the flagellum and cell morphogenesis in the protozoan parasite Trypanosoma brucei.”

We have used cellular electron tomography and serial block face scanning electron microscopy (SBF-SEM) to basal body and flagellum biogenesis. We demonstrate asymmetries in how connections between basal bodies are re-organised and have identified putative candidate proteins that may play a role in these connections. Using SBF-SEM we have also reconstructed individual cells through the cell cycle and provide quantitative analysis of the spatial and temporal organisation of flagellum biogenesis and other organelles through the cell cycle.

 

Invitation : Aksam Merched – Mircade U 1035

Mardi 29 novembre à 11 h
Salle de conférences IBGC, site de Carreire zone sud, université de Bordeaux

Martin Dutertre
Institut Curie, UMR 3348 CNRS, Team « RNA biology linked to DNA damage », Orsay, France.

“Alternative splicing and polyadenylation in tumor progression and drug response”

It is now well established that gene expression mis-regulation in cancer occurs at many steps beyond transcription initiation, especially pre-messenger RNA splicing and miRNA-mediated regulations. Firstly, the seminar will illustrate that gene expression can be controlled quantitatively at the level of transcription elongation, as well as the efficiency of pre-mRNA maturation (e.g., splicing). Secondly, qualitative regulation is not mediated only by alternative splicing, but also by alternative promoters and alternative polyadenylation. In particular, I will describe how genome-wide approaches reveal the widespread involvement of a novel mechanism of gene regulation involving alternative last exons (also called intronic polyadenylation) in two processes: tumor cell metastasis and response to genotoxic drugs.

 

Invitation : Alain Taïeb – U 1035

Jeudi 24 novembre à 11 h
Salle de conférences IBGC, site de Carreire zone sud, université de Bordeaux

Robert Ballotti
Responsable de l’équipe « Biologie et pathologies des cellules mélanocytaires »
au sein de l’unité Inserm 1065 – Nice

“Melanoma Initiating Cells, Senescence and Resistance: MITF Takes the Central Stage”

Among several hypotheses that might explain the resistance of melanoma to current therapies, one of the trendiest suggests the existence of a poorly differentiated melanoma cell population that would also account for the well recognized melanoma heterogeneity and invasiveness. This population, which displays an increase in mesenchymal and stemness phenotypes, can be referred as Melanoma Initiating Cells (MIC). Previous works, including ours, identified a low-MITF population endowed with all the properties of MIC, but in the absence of surface marker a full characterization of this population was not possible.
To overcome this hurdle, we engineered, using homologous recombination, a melanoma cell model expressing a MCherry flag upstream the exon 1 of the M-MITF. Using these cells, we have been able to isolate live Low-MCherry/low-MITF cells and to confirm their high tumorigenic potential, as well as their resistance to BRAF inhibitors.
DNA microarray analysis of Low-Mcherry vs High Mcherry allowed us to identify a repertoire of genes overexpressed in the MIC that is different from that found in after MITF silencing. Among these genes several surface markers were identified and we focused our attention on 2 of them; NGFR/CD271 that was already associated with MIC and ITGBL1 a poorly studied member of integrin family.
Finally, preliminary analysis of the histone methylation/acetylation marks in Low-MITF vs High-MITF cells involves epigenetic regulation in the control of the phenotypic switch between MIC and their differentiated progeny.
In summary, our data brought new insight into molecular mechanisms controlling melanoma cell plasticity, tumorigenicity and resistance to drugs. Further investigations, will allow evaluating the importance these surface markers and epigenetic modifications in melanoma treatment.

 

Invitation : Isabelle Vigon – Inserm U 1035

Mardi 22 novembre à 11 h
Salle de conférences IBGC, site de Carreire zone sud, université de Bordeaux

Françoise Pflumio
CEA – Laboratoire des cellules Souches Hématopoïétiques et des Leucémies – LSHL

“Interactions between T-ALL and the BM microenvironment influence the leukemic development and the resistance to certain drugs”

T-cell acute lymphoblastic leukemia (T-ALL) is a T-cell progenitor malignancy, which mainly affects children and young adults. In T-ALL development, leukemic cells home to various bone marrow (BM) sites that include adipocyte-poor (red marrow) and adipocyte-rich (yellow marrow) niches. Using xenografts of human and mouse T-ALL, we explored the impact of these distinct BM sites on leukemic cells. We demonstrate that T-ALL cells invade all studied BM sites but with different kinetics depending on those sites. T-ALL cells also displayed BM-niche specific characteristics in terms of cell surface phenotype, metabolism, cell cycle progression albeit genomic abnormalities were similar wherever the T-ALL cells were isolated from. Overall, our current results demonstrate that distinct BM sites differentially orchestrate T-ALL development and during my talk I will also show how such BM niches may participate into chemo-resistance.

 

Invitation : Julie Dechanet-Merville – ALisay CNRS UMR 5164

Jeudi 27 octobre à 13 h 30
Salle de conférences IBGC, site de Carreire zone sud, université de Bordeaux

Ceri Fielding
Treasurer, South Wales British Society of Immunology Group
Cytomegalovirus and Adenovirus Research Group
Division of Infection and Immunity
College of Biomedical and Life Sciences
Cardiff University

“Investigating Human Cytomegalovirus immune evasion using proteomics”

Human cytomegalovirus (HCMV) infection results in significant morbidity and mortality in immunocompromised patients and is the major infectious cause of congenital birth defects. HCMV has a major impact on the phenotype of the host’s immune system, including natural killer (NK) cells, and encodes many immuno-modulatory genes. Many of these belong to several families of related genes, of which one, the US12 family, consists of ten sequentially arranged genes (US12-21). Specific US12 family members have identified roles in endothelial cell tropism and NK cell evasion. We set out to test our hypothesis that the US12 family represents a gene expansion resulting from immune selective pressure and that the entire family has a role in NK cell evasion. We now demonstrate that the US12 family selectively targets plasma membrane proteins and plays key roles in regulating NK ligands, adhesion molecules and cytokine receptors using a systematic multiplexed proteomics approach that quantified ~1,300 cell surface and ~7,200 whole cell proteins. Novel NK cell evasion functions were identified for four US12 family members: US12, US14, US18 and US20. Critically, US18 and US20 work in concert to target the chief ligand for the NK cell activating receptor NKp30, B7-H6. The US12 family therefore represents a major hub of immune regulation during HCMV infection.

 

Invitation : Pierre Soubeyran – Action U 1218

Lundi 17 octobre à 11 h
Salle de conférences IBGC, site de Carreire zone sud, université de Bordeaux

Jean-Marc Lemaître
INSERM U1183 “Cellules souches, plasticité cellulaire, médecine régénératrice et immunothérapies” – Montpellier

“Exploring Genome and Cell Plasticity in Ageing”

The global project of the team of Jean-Marc Lemaître is to explore basic genetic and epigenetic mechanisms underlying tissue regeneration, a process that takes place from early development through the entire lifetime and decreasing in the elderly. We aim to unravel and to manipulate age-related molecular pathways for efficient somatic cell reprogramming and to apply this knowledge to rejuvenation of cell physiology and improve tissue regeneration in chronic and aged related diseases, which is a major objective of regenerative medicine.

 

Invitation : Frédéric Bringaud – UMR CNRS 5234

Vendredi 14 octobre à 11 h
Salle de Conférence RMSB

Paul Michels
Centre for Immunity, Infection and Evolution (CIIE) and Centre for Translational and Chemical Biology (CTCB), School of Biological Sciences, The University of Edinburgh, The King’s Buildings – Scotland

Occurrence and functions of peroxisomes in trypanosomatids and other protists.”

Paul Michelsa, Toni Gabaldónb, Michael Gingerc
a School of Biological Sciences, University of Edinburgh, UK
b The Barcelona Institute of Science and Technology, Spain
c Department of Biological Sciences, University of Huddersfield, UK

Peroxisomes can be detected in representatives of all eukaryotic superphyla. The similar morphology and mode of biogenesis of the organelles indicate a monophyletic origin within the Last Eukaryotic Common Ancestor (LECA). Despite a common origin and shared morphological features, peroxisomes from different organisms show a remarkable diversity of enzyme content. Moreover, the metabolic processes present in the organelles can vary importantly dependent on nutritional or developmental conditions. Peroxisomes probably originated from the endoplasmic reticulum (ER); the common involvement of all peroxisomes in lipid metabolism, notably H2O2-dependent fatty-acid oxidation suggests that sequestering a H2O2-producing FAD-dependent acyl-CoA oxidase from the ER in a newly formed organelle, limiting the rate of oxidative damage within the ER, has been the evolutionary driver for the peroxisome’s origin. Subsequent evolution of peroxisomes in different lineages involved multiple acquisitions of metabolic processes – often involving retargeting enzymes from other cell compartments – and losses. Available information about peroxisomes in protists, albeit scarce, and new bioinformatics data indicate a striking diversity among free-living and parasitic protists from different phylogenetic supergroups. Peroxisomes in only some protists show major involvement in H2O2-dependent metabolism, as in peroxisomes of mammalian, plant and fungal cells. Within the excavate supergroup of eukaryotes, the presence of glycolytic and gluconeogenic enzymes inside peroxisomes is characteristic for kinetoplastids (parasites such as Trypanosoma and Leishmania and the free-living Bodo) and diplonemids (free-living protists abundantly present in oceans), where the organelles are hence called glycosomes. The role of glycosomes in trypanosomatid metabolism, and the changes of the organelles’ enzyme content during the parasites’ life cycle, have been studied in great detail. Regarding other excavate protists, bioinformatics analysis suggests the presence of more ‘classical’ peroxisomes in the free-living Naegleria, whereas the parasites Giardia and Trichomonas have lost peroxisomes altogether. Among alveolates (including parasites such as Plasmodium, Toxoplasma, Cryptosporidium) and amoebozoans (free-living Dictyostelium, parasitic Acanthamoeba and Entamoeba) patterns of peroxisome loss are more complicated. Often, a link is apparent between the niches occupied by the protists, nutrient availability, and the absence of the organelles or their presence with a specific enzymatic content.

 

Invitation : Thomas Pradeu – ALisay CNRS UMR 5164

Lundi 10 octobre à 11 h
Salle de Conférences de l’Espace Santé – Carreire Zone Nord

Patrick Forterre
INSERM U1060 (Laboratoire CarMeN), Lyon

“The concept of virus and the definition of life”

Pendant longtemps, la plupart des biologistes ont considéré les virus comme des sous-produits de l’évolution biologique qui n’avaient pu jouer qu’un rôle mineur dans l’histoire du monde vivant. Cette situation a progressivement changé ces dernières années à la suite de plusieurs avancées dans différents domaines de la biologie. Les écologistes moléculaires ont mis en évidence l’extraordinaire abondances des particules virales et des gènes viraux dans l’environnements, les biologistes structuralistes ont mis en évidence des relations de parenté inattendues entre virus infectants des organismes appartenant à des domaines cellulaires différents (archées, bactéries ou eucaryotes) en déterminant la structure des protéines formant les capsides virales. Dans le même temps, l’étude des virus d’archées a révélé un monde fascinant de virus différents des virus connus précédemment chez les bactéries et les eucaryotes. Pour couronner le tout, la découverte des virus géants a frappé l’imagination de la communauté scientifique en révélant l’existence de virus dont les génomes sont plus grands que ceux de nombreuses bactéries et archées. Toutes ces découvertes ont relancés l’intérêt pour les virus et reposé la question de leur nature – vivant ou non – et de la définition de la vie elle-même. Les virus ont souvent été assimilé à leur virion (la particule virale) ce qui semblait justifier leur exclusion du monde vivant. J’ai récemment proposé le concept de « cellule virale » pour mettre l’accent sur la partie cellulaire du cycle viral qui implique la transformation de tout ou parti de l’hôte infecté en organisme viral « vivant ». L’étude de l’évolution des microorganismes montre toutefois qu’il n’est pas possible de définir rigoureusement un organisme vivant par rapport à un organite cellulaire ou encore un virus « vivant » par rapport à un plasmide « non vivant ». Pour dépasser cette impasse philosophique, j’ai proposé, de façon un peu provocatrice, de considérer comme vivant toutes les entités biologiques (protéines, chromosomes, plasmides) qui participent à un processus vivant. Il reste alors à définir ce que l’on entend par « entités biologiques » et « processus vivant ».

For years, most biologists considered viruses as by-products of biological evolution that could have only play a minor role in the history of the living world. This has gradually changed in recent years as a result of several advances in different fields of biology. The molecular ecologists have highlighted the extraordinary abundance of viral particles and viral genes in the environment, the structuralists biologists have shown unexpected kinship between viruses infecting organisms belonging to different cellular domains (archaea, bacteria or eukaryotic) determining the structure of the proteins forming the viral capsid. At the same time, the study of archaeal virus revealed a fascinating world of different viruses previously unknown in bacteria and eukaryotes. To top it all, the discovery of giant virus has caught the imagination of the scientific community by revealing the existence of viruses whose genomes are greater than those of many bacteria and archaea. All these findings have revived interest in viruses and rested the issue of their nature – living or not – and the definition of life itself. Viruses have often been likened to their virion (virus particle) which seemed to justify their exclusion from the living world. I recently proposed the concept of “virocell” to focus on the cellular step of the viral cycle that involves the transformation of all or part of the infected host in viral organism “living.” The study of the evolution of microorganisms shows however that it is not possible to rigorously define a living organism versus a cellular organelle or a “live” virus compared to a plasmid “not alive”. To overcome this philosophical impasse, I proposed, in a somewhat provocative way, to consider all living biological entities (proteins, chromosomes, plasmids) that participate in a living process to be alive. It remains to define what is meant by “biological entities” and “living process”.


Invitation : Manuel Rojo – UMR CNRS 5095 IBGC

Mardi 4 octobre à 11 h
Salle de conférences IBGC, site de Carreire zone sud, université de Bordeaux

Jennifer Rieusset
INSERM U1060 (Laboratoire CarMeN), Lyon

“Rôle des interactions entre le réticulum endoplasmique et la mitochondrie dans le contrôle du métabolisme hépatique et dans les maladies métaboliques.”

Les maladies métaboliques telles que l’obésité et le diabète de type 2 (DT2) sont associées à un excès de nutriments et à une inflexibilité métabolique. Les mitochondries et le réticulum endoplasmique (RE) sont deux organites intracellulaires importants sensibles aux nutriments, et leurs dysfonctionnements ont été largement et indépendamment associés au développement des maladies métaboliques. Les deux organites interagissent au niveau de point de contact appelés MAMs (mitochondria-associated membranes), afin d’échanger des lipides et du calcium et contrôler la signalisation et le métabolisme cellulaire. Nos données récentes indiquent que les MAMs pourraient être un carrefour important du métabolisme hépatique intégrant à la fois des signaux nutritionnels et hormonaux.
Au cours de ma présentation, je présenterai nos travaux récents démontrant que les MAMs permettent au foie, d’une part d’adapter la dynamique et la fonction mitochondriale à la disponibilité en glucose, et d’autre part de contrôler l’action de l’insuline, suggérant un rôle clé des MAMs dans les adaptations du métabolisme hépatique aux changements nutritionnels. Enfin, j’aborderai comment un défaut de communication entre les deux organites pourrait participer à l’insulino-résistance hépatique et à l’inflexibilité métabolique rencontré au cours de l’obésité et du DT2.


Invitation : Nathalie Schmitt – CNRS UMR 5164

Jeudi 29 septembre à 13 h 30
Salle de conférences RMSB, bât 4, rez-de-chaussée, site de Carreire zone nord, université de Bordeaux

Dominique Kaiserlian
DR1 INSERM, INSERM-U1060, Lyon

“The gut-liver axis in orchestrating tolerance and immunity”

The intestinal mucosal immune system is naturally geared toward immune tolerance to intestinal antigens derived from the diet and the microbiota to maintain tissue homeostasis and prevent chronic allergic and inflammatory diseases. We have studied the in vivo immune mechanisms behind tolerance and immunity to intestinal antigens and showed the division of labour between the intestine and the liver both for inducing T cell tolerance and prevention of allergy and for induction of IgA responses in different settings.


Invitation : Bertrand Daignan-Fornier – IBGC UMR CNRS 5095

Jeudi 22 septembre à 14 h 30
Salle de conférences de l’IBGC, site de Carreire zone sud, université de Bordeaux


Manuel Mendoza
Cytokinesis and Chromosome Segregation Group
Cell and Developmental Biology Programme
Centre de Regulació Genòmica (CRG)
Barcelona – Spain

“Nuclear Division and Organisation”

My laboratory studies fundamental principles of cell division, using budding yeast as our main model system. We have two major interests. First, we study how chromosome segregation and cytokinesis are coordinated with each other. I will present our recent findings on the Aurora-B-dependent abscission checkpoint (NoCut), which delays completion of cytokinesis in response to anaphase chromatin bridges. In particular, I’ll show that NoCut provides time for chromatin bridge resolution after replicative stress, thus preventing cytokinesis-dependent DNA damage and promoting genome stability. Second, we study how nuclear re-organization is established after asymmetric cell division to regulate cell fate. We discovered an asymmetrically segregated cell fate determinant, the lysine deacetylase Hos3, which is recruited to the periphery of the daughter cell nucleus during mitosis. Hos3 associates with nuclear pores specifically in daughter cells, where it restrains entry into the next cell cycle by multiple mechanisms, including regulation of nucleo-cytoplasmic transport and modulation of gene positioning. Similar mechanisms might establish asymmetries in nuclear organisation and control cell proliferation in multicellular organisms.


Invitation : Frédéric Bringaud – UMR CNRS 5234

Mardi 19 juillet 2016 à 11 h 00
Salle de conférences de l’IBGC

Karine Frénal
Département de microbiologie et médecine moléculaire – Université de Genève

“Function of actomyosin systems in Toxoplasma gondii”

The phylum Apicomplexa includes a large and diverse group of obligate intracellular parasites such as Plasmodium species responsible for malaria and Toxoplasma gondii, the causative agent of toxoplasmosis. These parasites share a unique form of actomyosin-based gliding motility that is essential for migration across biological barriers, entry into host cells and egress from infected cells. The glideosome is known as the conserved molecular machinery located in the parasite pellicle and driving motility. We carried out a detailed dissection of the interactions implicated in the formation of the complex in Toxoplasma gondii. This led us to the identification of the determinants responsible for the assembly and anchoring of the glideosome and forced us to revisit the topology of the complex within the pellicle. In addition, this led us to the identification of three other complexes and a global understanding of the machineries implicated in motility, invasion and egress.

With 11 myosins, Toxoplasma gondii possesses the largest and most diverse repertoire of myosin motors within the Apicomplexans. We have recently undertaken the function of the other uncharacterized myosins through the study of the myosin-specific chaperone TgUNC. Although several myosins appeared dispensable without noticeable phenotype, two of them were found responsible for the constriction of the basal complex and the maintenance of an intra-vacuolar connection between the parasites. This connection is responsible for the extremely tight synchronicity of division of the parasites residing within the parasitophorous vacuole and is also likely responsible for the delayed death phenotype.


Invitation : Benjamin Faustin – Alysai CNRS UMR 5164

Jeudi 7 juillet 2016 à 11 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Maya Saleh, Ph. D.
William Dawson Scholar
Director, Inflammation and Cancer Program
Associate Professor
Department of Medicine
McGill Life Sciences Complex
Bellini Pavilion, Room 364
3649 Promenade Sir William Osler
Montreal, Qc, Canada H3G 0B1

“Crosstalk of innate immunity and cell death pathways in inflammatory diseases and cancer”.

One important question in immunology is how the organism senses the presence of an invading microorganism, tissue injury, organ malfunction or cellular transformation. Pattern-recognition receptors fulfill this task, often through large macromolecular complexes known as “inflammasomes”, and prime adaptive immunity to establish immunological memory. The identification of cognate ligands for these receptors in physiological and pathological contexts and the characterization of their effector functions in infectious and sterile-inflammatory diseases is needed to set the stage for the development of therapeutics to cure these diseases. My laboratory is studying these key pathways of inflammation, innate immunity and cell death (apoptosis, pyroptosis and necroptosis) in inflammatory bowel disease, dermatitis, pulmonary inflammation, metabolic disorders and cancer. We have established proteomics approaches and large-scale genome-wide RNA interference screening platforms to identify key targets in innate immunity and cell death pathways, and are employing novel animal models to identify and validate such targets in vivo.


Invitation : Thomas Daubon – Inserm U 1029

Jeudi 30 juin 2016 à 11 h 30
Salle de conférences de la Plateforme Génomique Fonctionnelle

Hrvoje Miletic
K.G. Jebsen Brain Tumor Research Centre, University of Bergen, Norway
Department of Biomedicine, University of Bergen, Norway
Department of Pathology, Haukeland University Hospital, Bergen, Norway

“Clonal and functional heterogeneity of EGFRs in glioblastoma development”

EGFR gene amplification is observed in approximately 40% of glioblastoma (GBM) biopsies, and genetic aberration to EGFR at large has been described to occur in excess of 50%. Detected in half of GBMs harboring EGFR amplification, the most prominent EGFR mutation arises upon deletion of exons 2 through 7 to generate the constitutively active truncation mutant EGFRvIII. Our lab has developed a clinically relevant in vivo xenograft model derived from patient biopsies in which we are able to accurately study EGFR signaling in human GBM. In particular, we showed that wild-type (wt) EGFR amplification and activation promotes invasion and development of GBM independent of angiogenesis. By analyzing the clonal evolution of EGFRs in patient samples we showed that EGFRvIII mutations evolve later in tumorigenesis compared to EGFR amplification. Overexpression of EGFRvIII, but not wtEGFR, in patient-derived xenograft models promoted angiogenic tumor growth through activation of Src. Thus, wtEGFR and EGFRvIII drive aggressive tumor growth of GBMs by promoting invasion and angiogenesis through distinct signaling pathways.


Invitation : Jean-Paul di Rago – IBGC UMR CNRS 5195

Mercredi 29 juin 2016 à 11 h 00
Salle de conférences de l’IBGC

Myriam Bourens
Depts of Neurology and Biochemistry & Molecular Biology
University of Miami Miller School of Medicine, USA.

“CMC1 participates in the assembly of a complicated mitochondrial protein complex : the human cytochrome c oxidase.”

Defects in mitochondrial respiratory chain complex IV (CIV- Cytochrome c oxidase) biogenesis are a frequent cause of encephalocardiomyopathies in humans. CIV biogenesis involves 13 subunits of dual genetic origin, and multiple nucleus-encoded assembly factors. CIV assembly begins with the maturation of COX1 subunit by various assembly factors, among them COA3 and COX14 bind newly synthesized COX1 and have been proposed to control its rate of synthesis.
Here, we have disclosed that the intermembrane space twin-CX9C protein CMC1 is implicated in COX1 maturation. A TALEN-mediated CMC1 Knock-out human HEK293T cell line displayed normal COX1 synthesis but decreased CIV activity owing to instability of newly synthetized COX1. We demonstrate that CMC1 forms a stable complex with COX1, COA3 and COX14 prior to the incorporation of COX4 and COX5a subunits. Furthermore, formation and stability of the CMC1 complex is independent of other COX1 assembly factors COX10, COX11, MITRAC7 and SURF1. Our data indicates that CMC1 sets an early quality control checkpoint during CIV assembly and regulates the turnover of newly synthesized COX1 without affecting its rate of synthesis.


Invitation : Harald Wodrich –
UMR CNRS 5234

Mardi 28 juin 2016 à 11 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Mario Schelhaas
Institute of Molecular Virology & Institute of Medical Biochemistry
Virus Endocytosis Group

“The alpha and omega of Human papillomavirus entry: from structural priming after binding to nuclear delivery of viral genomes during mitosis”

 
Human papillomaviruses (HPVs) are a large family of small, nonenveloped DNA viruses that cause a variety of infections ranging from a asymptomatic to malignant outcomes. These viruses infect squamous mucosal or skin epithelia. Entry occurs into the basal stem cells, whereas viral replication and assembly is linked to the differentiation program of epithelia.
The initial entry of HPVs is rather unusual when compared to other viruses. It involves a series of structural changes within virions upon binding that primes the virus for engagement of an elusive secondary receptor, uptake by a novel endocytic pathway, intracellular sorting towards the trans-Golgi-network, and import of viral genomes during mitosis. Here, I will present an overview of the entry pathway of HPVs, and highlight our recent results on the functions and mechanisms of structural priming for receptor engagement, as well as the cause and consequences of interactions that occur to facilitate tethering of the viral genome to mitosis chromatin for nuclear import.

Invitation : Jean-Paul di Rago – IBGC UMR CNRS 5195

Mercredi 29 juin 2016 à 11 h 00
Salle de conférences de l’IBGC

Myriam Bourens
Depts of Neurology and Biochemistry & Molecular Biology
University of Miami Miller School of Medicine, USA.

“CMC1 participates in the assembly of a complicated mitochondrial protein complex : the human cytochrome c oxidase.”

Defects in mitochondrial respiratory chain complex IV (CIV- Cytochrome c oxidase) biogenesis are a frequent cause of encephalocardiomyopathies in humans. CIV biogenesis involves 13 subunits of dual genetic origin, and multiple nucleus-encoded assembly factors. CIV assembly begins with the maturation of COX1 subunit by various assembly factors, among them COA3 and COX14 bind newly synthesized COX1 and have been proposed to control its rate of synthesis.
Here, we have disclosed that the intermembrane space twin-CX9C protein CMC1 is implicated in COX1 maturation. A TALEN-mediated CMC1 Knock-out human HEK293T cell line displayed normal COX1 synthesis but decreased CIV activity owing to instability of newly synthetized COX1. We demonstrate that CMC1 forms a stable complex with COX1, COA3 and COX14 prior to the incorporation of COX4 and COX5a subunits. Furthermore, formation and stability of the CMC1 complex is independent of other COX1 assembly factors COX10, COX11, MITRAC7 and SURF1. Our data indicates that CMC1 sets an early quality control checkpoint during CIV assembly and regulates the turnover of newly synthesized COX1 without affecting its rate of synthesis.


Invitation : Harald Wodrich –
UMR CNRS 5234

Mardi 28 juin 2016 à 11 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Mario Schelhaas
Institute of Molecular Virology & Institute of Medical Biochemistry
Virus Endocytosis Group

“The alpha and omega of Human papillomavirus entry: from structural priming after binding to nuclear delivery of viral genomes during mitosis”

Human papillomaviruses (HPVs) are a large family of small, nonenveloped DNA viruses that cause a variety of infections ranging from a asymptomatic to malignant outcomes. These viruses infect squamous mucosal or skin epithelia. Entry occurs into the basal stem cells, whereas viral replication and assembly is linked to the differentiation program of epithelia.
The initial entry of HPVs is rather unusual when compared to other viruses. It involves a series of structural changes within virions upon binding that primes the virus for engagement of an elusive secondary receptor, uptake by a novel endocytic pathway, intracellular sorting towards the trans-Golgi-network, and import of viral genomes during mitosis. Here, I will present an overview of the entry pathway of HPVs, and highlight our recent results on the functions and mechanisms of structural priming for receptor engagement, as well as the cause and consequences of interactions that occur to facilitate tethering of the viral genome to mitosis chromatin for nuclear import.


Invitation : Nathalie Schmitt – UMR CNRS 5164

Jeudi 23 juin 2016 à 14 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Hideki Ueno, MD, PhD
Professor, Department of Microbiology
Professor, Global Health and Emerging Pathogens Institute
Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

“Regulation of Antibody Responses in Humans”

T follicular helper (Tfh) cells represent the major CD4+ T cell subset providing help to B cells. Tfh cells are essential for the generation of high-affinity memory B cells through the germinal center (GC) formation. CD4+ T cells also provide help to B cells at extrafollicular sites, and induce their differentiation into plasma cells that contribute to the early generation of specific antibodies after antigen challenge. These extrafollicular helper cells share developmental mechanisms, phenotypes, and functional properties with Tfh cells.

Tfh response needs to be regulated, as both insufficient and increased Tfh responses cause health problems. Insufficient Tfh response causes failure in the development of antibody responses, for example in response to vaccination. Increased Tfh response causes autoimmunity by activating self-reactive B cells and promoting the generation of autoantibodies. Therefore, understanding the biology of human Tfh cells is essential to define the mechanisms responsible for altered antibody responses in humans. In my seminar, I will briefly summarize the current knowledge on human Tfh cells, and discuss how functionally distinct Tfh cell subsets differentially regulate antibody responses in humans.


Invitation : Julie Dechanet-Merville –
UMR CNRS 5164

Mardi 21 juin 2016 à 14 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Richard D. Lopez, MD
Associate Professor of Medicine
Division of Cellular Therapy/Bone Marrow Transplantation
Duke University School of Medicine
Durham, North Carolina, USA

“Using a model of HPV infection to examine how cytolytic gd-T cells interact with target cells”


Invitation : Jean-Paul di Rago – IBGC UMR CNRS 5195

Vendredi 10 juin 2016 à 11 h 00
Salle de conférences de l’IBGC

Patrice X. Petit
CNRS, INSERM 1124, University Paris-Descartes, Paris, France.

BARTH SYNDROME:
CARDIOLIPIN ALTERATIONS LINKED TO TAFAZZIN MUTATIONS LEADS
TO APOPTOSIS AND MITOPHAGY ALTERATIONS”

Tafazzin is a unique phospholipid transacylase that catalyzes the remodeling of cardiolipin a mitochondrial phospholipid of required for oxidative phosphorylation. Tafazzin mutation reduces cardiolipin (CL), changes their acyl chain composition, impairs mitochondrial function, and causes dilated cardiomyopathy in Barth syndrome, a rare and often fatal X-linked genetic disorder accompanied by aciduria, neutropenia, and myocardial noncompaction1.
However, the molecular mechanisms underlying the cause of mitochondrial dysfunction in Barth syndrome remain poorly understood. Taking into account recent findings, i.e. bioenergetic perturbations1, ROS production2, cell cycle disregulation3, that accompagnied tafazzin gene mutations or knockdown experiments, we have focused on the effect of modified CL on mitochondrially driven apoptosis and mitophagic processes.
Using Barth syndrome patient-derived cells and HeLa cells in which tafazzin was knocked down, we show that cardiolipin is required for apoptosis. Cardiolipin provides an anchor and activating platform for caspase-8 translocation to, and embedding in, the mitochondrial membrane4.
Consistent with a key role of mitophagy in mitochondria quality control, impaired bioenergetic and oxidative stress linked to CL non-maturation lead to impaired mitophagy.
Together, these findings provide key insights on mitochondrial dysfunction in Barth syndrome, suggesting that pharmacological restoration of mitophagy may provide a novel treatment for this lethal condition.

1Saric A, Andreau K, Armand A-S, Møller IM and PX Petit. Barth Syndrome: From mitochondrial dysfunctions associated with aberrant production of reactive oxygen species to puripotent stem cell studies (2016) Frontiers in Genetics 6, article 356, 1-26.
2Gonzalvez F, D’Aurelio M, Boutant M, Moustapha A, Puech JP, Landes T, Arnauné-Pelloquin L, Vial G, Taleux N, Slomianny C, Wanders RJ, Houtkooper RH, Bellenguer P, Møller IM, Gottlieb E, Vaz FM, Manfredi G, Petit PX. Barth syndrome : cellular compensation of mitochondrial dysfunction and apoptosis inhibition due to changes in cardiolipin remodelling linked to Tafazzin gene mutation . Biochim Biophys Acta. 2013 1832 (8): 1194-1206.
3He Q, Wang M, Harris N, Han X. Tafazzin knockdown interrupts cell cycle progression in cultured neonatal ventricular fibroblasts. Am J Physiol Heart Circ Physiol. 2013 1; 305(9): H1332-1343.
4Gonzalvez F, Schug ZT, Houtkooper RH, MacKenzie ED, Brooks DG, Wanders RJ, Petit PX, Vaz FM, Gottlieb E. Cardiolipin provides an essential activating platform for caspase-8 on mitochondria. J Cell Biol. 2008 183(4): 681-696.


Invitation : Rodrigue Rossignol – Inserm U 1211 MRGM

Jeudi 9 juin 2016 à 11 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Minho Shong, M.D., Ph.D.
Chungnam National University, Korea

“Mitochodrial Proteostasis, unfolded protein response and systemic energy metabolism”

Recent in vivo studies in C. elegans and Drosophila revealed that UPRmt activation by inhibition of mitochondrial electron transport chain (ETC) functions increases lifespan (Houtkooper RH et al., Nature 2013; Durieux J et al., Cell 2011) This effect of ETC inhibition on longevity is modulated by cell-autonomous and cell-non-autonomous factors, known as mitokines, which may promote metabolic homeostasis. However, extrapolation of these studies into mammalian systems is extremely difficult because generalized impairment of ETC function in mice uniformly results in progressive deterioration of organ functions and premature death. To investigate whether the role of cell-non-autonomous mitokine networks is conserved in mammalian systems, we designed a spatio-temporal approach for gene expression and secretome analysis in mice with tissue-specific UPRmt activation.
Recently, we successfully generated and demonstrated relevant mouse models of tissue-specific UPRmt activation and ETC deficiency that are reminiscent of complex human disorders, e.g., neurodegeneration (Kim et al., Cell Metab, 2012), Parkinson’s disease, insulin resistance (Ryu et al., PLOS Genetics, 2013), and type 1 diabetes (Kim et al., Diabetologia, 2015). These models are based on tissue-specific knockout (KO) of Crif1, which encodes a factor required for biogenesis of ETC subunits. Loss of Crif1 resulted in abnormal proteostasis in the mitochondrial matrix and triggered the mitochondrial unfolded protein response (UPRmt). Preliminary observations on phenotypes of tissue-specific Crif1-deficient mice revealed that Crif1-deficient cells and tissues express unique UPRmt activation e.g., adaptive transcriptomic changes and secretome responses (mitokines). which can be considered to be part of the phenomenon of “mitohormesis” (Yun J and Finkel T, Cell Metab, 2014). Based on these observations, we postulated that tissue-specific UPRmt and mitokine responses are critical cell-non-autonomous modifiers in disease progression, and that individual mitokines may act as disease markers and potential therapeutic targets in complex human disorders.


Invitation : Alain Taïeb et François Moisan – Inserm U 1035

Jeudi 2 juin 2016 à 14 h 30
Salle de conférences de l’IBGC

Eddy Pasquier
Aix-Marseille Université

“Drug repurposing to improve the treatment of refractory cancers”

Drug resistance is one the main challenges of modern oncology. Meanwhile, the cost of newly developed anti-cancer drugs is dramatically increasing, so much so that cancer care will soon become unaffordable for a majority of patients. In this context, drug repurposing – using already-approved drugs for new medical applications – represents a unique opportunity to rapidly develop cheaper anti-cancer treatments that may be able to bypass or overcome resistance mechanisms.

The discovery of the efficacy of propranolol, a non-selective adrenergic receptor antagonist, in treating severe hemangioma of infancy [Léauté-Labrèze et al., New England J Med 2008], has led us to investigate the potential repurposing of propranolol for the treatment of malignant tumours. We thus showed that propranolol, and other beta-blockers, were able to increase the efficacy of certain types of chemotherapy agents in laboratory models of breast cancer, neuroblastoma and angiosarcoma [Pasquier et al., Oncotarget 2011; British J Cancer 2013; EBioMedicine 2016]. This work has led to a number of clinical trials currently underway and may ultimately improve the survival of cancer patients. Besides our work on beta-blockers, we have recently developed an unbiased approach that combines high-throughput drug and siRNA screening based on synthetic lethality to identify and validate novel therapeutic targets in refractory cancers. We have first used this methodology in glioblastoma multiforme with promising results. We are now working towards applying this type of approach for the personalization of anti-cancer treatments.


Invitation : Manuel Rojo
– IBGC UMR CNRS 5195

Jeudi 2 juin 2016 à 11 h 00
Salle de conférences de l’IBGC

Thomas Rival
Campus de Luminy – IBDM – CNRS/Aix-Marseille Université

“Alterations of mitochondrial fusion in Charcot-Marie-Tooth neuropathy”


In this talk, I will describe how we have used the drosophila model system to characterize pathogenic alleles of mitofusin that are known to cause Charcot-Marie-Tooth type 2A disease in human.


Invitation : Sven Saupe
– IBGC UMR CNRS 5195

Mercredi 1er juin 2016 à 14 h 00
Salle de conférences de l’IBGC

N. Louise Glass
Department of Plant and Microbial Biology and The Energy Biosciences Institute,
The University of California, Berkeley, CA, USA

“Interplay between self and nonself recognition mechanisms regulate chemotropic interactions, cell fusion and establishment of multicellularity in fungi”

The origin of multicellularity allowed increases in size and complexity in organisms via differentiation of cell lineages and is one of the major transitions in evolution. The multicellular network of hyphae, which is the somatic growth habit of filamentous fungi, provides as excellent system to investigate processes associated with multicellular development. In the model filamentous fungus Neurospora crassa, somatic fusion between genetically identical cells confers fitness benefits and is a highly regulated process associated with early colony establishment and hyphal network formation. Chemotropic interactions and cell fusion are regulated by components of a MAP kinase cascade, a scaffold protein and two target transcription factors. Chemotropic interactions between genetically identical cells are associated with dynamic oscillation of the MAPK components from the cytoplasm to cell tips.
Using population genomics on wild isolates of N. crassa, we determined that chemotropic interactions between genetically non-identical cells was associated with communication groups (CGs); cells of identical CG interact, while cells of different CG ignore each other. By bulked segregant analysis and high throughput sequencing, we identified two polymorphic genes (doc-1 and doc-2) that are under balancing selection and that are necessary and sufficient to confer CG phenotype. During chemotropic interactions between genetically identical cells, DOC1 co-oscillates with components of the MAP kinase complex. These data indicate that self and nonself interactions during chemotropic interactions and cell fusion are linked and that an interplay between these two systems is important for cooperation and establishment of multicellularity.

Heller J, Zhao J, Rosenfield G, Kowbel DJ, Gladieux P, Glass NL (2016).
Characterization of greenbeard genes involved in long-distance kind discrimination in a microbial eukaryote. PLoS Biol. 2016 14(4):e1002431.

Zhao J, Gladieux P, Hutchison E, Bueche J, Hall C, Perraudeau F, Glass NL (2015).
Identification of allorecognition loci in Neurospora crassa by genomics and evolutionary approaches. Mol Biol Evol. 32(9):2417-32.

Jonkers W, Leeder AC, Ansong C, Wang Y, Yang F, Starr TL, Camp DG 2nd, Smith RD, Glass NL (2014). HAM-5 functions as a MAP kinase scaffold during cell fusion in Neurospora crassa. PLoS Genet.10 (11):e1004783.


Invitation : Jean-Paul di Rago – IBGC UMR CNRS 5195

Jeudi 26 mai 2016 à 11 h 00
Salle de conférences de l’IBGC

Patrice X. Petit
CNRS, INSERM 1124, University Paris-Descartes, Paris, France.

BARTH SYNDROME:
CARDIOLIPIN ALTERATIONS LINKED TO TAFAZZIN MUTATIONS LEADS
TO APOPTOSIS AND MITOPHAGY ALTERATIONS”

Tafazzin is a unique phospholipid transacylase that catalyzes the remodeling of cardiolipin a mitochondrial phospholipid of required for oxidative phosphorylation. Tafazzin mutation reduces cardiolipin (CL), changes their acyl chain composition, impairs mitochondrial function, and causes dilated cardiomyopathy in Barth syndrome, a rare and often fatal X-linked genetic disorder accompanied by aciduria, neutropenia, and myocardial noncompaction1.
However, the molecular mechanisms underlying the cause of mitochondrial dysfunction in Barth syndrome remain poorly understood. Taking into account recent findings, i.e. bioenergetic perturbations1, ROS production2, cell cycle disregulation3, that accompagnied tafazzin gene mutations or knockdown experiments, we have focused on the effect of modified CL on mitochondrially driven apoptosis and mitophagic processes.
Using Barth syndrome patient-derived cells and HeLa cells in which tafazzin was knocked down, we show that cardiolipin is required for apoptosis. Cardiolipin provides an anchor and activating platform for caspase-8 translocation to, and embedding in, the mitochondrial membrane4.
Consistent with a key role of mitophagy in mitochondria quality control, impaired bioenergetic and oxidative stress linked to CL non-maturation lead to impaired mitophagy.
Together, these findings provide key insights on mitochondrial dysfunction in Barth syndrome, suggesting that pharmacological restoration of mitophagy may provide a novel treatment for this lethal condition.

1Saric A, Andreau K, Armand A-S, Møller IM and PX Petit. Barth Syndrome: From mitochondrial dysfunctions associated with aberrant production of reactive oxygen species to puripotent stem cell studies (2016) Frontiers in Genetics 6, article 356, 1-26.
2Gonzalvez F, D’Aurelio M, Boutant M, Moustapha A, Puech JP, Landes T, Arnauné-Pelloquin L, Vial G, Taleux N, Slomianny C, Wanders RJ, Houtkooper RH, Bellenguer P, Møller IM, Gottlieb E, Vaz FM, Manfredi G, Petit PX. Barth syndrome : cellular compensation of mitochondrial dysfunction and apoptosis inhibition due to changes in cardiolipin remodelling linked to Tafazzin gene mutation . Biochim Biophys Acta. 2013 1832 (8): 1194-1206.
3He Q, Wang M, Harris N, Han X. Tafazzin knockdown interrupts cell cycle progression in cultured neonatal ventricular fibroblasts. Am J Physiol Heart Circ Physiol. 2013 1; 305(9): H1332-1343.
4Gonzalvez F, Schug ZT, Houtkooper RH, MacKenzie ED, Brooks DG, Wanders RJ, Petit PX, Vaz FM, Gottlieb E. Cardiolipin provides an essential activating platform for caspase-8 on mitochondria. J Cell Biol. 2008 183(4): 681-696.


Invitation : Hélène Dumay-Odelot IECB et Jean Rosenbaum – Inserm U 1053

Mercredi 25 mai 2016 à 11 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Michel Werner
Institut de Biologie et Technologie – SaclayDépartement de Biologie des Génomes, I2BC – 91191 Gif-sur-Yvette Cedex

“The central role of Mediator in the coordination of pre initiation complex formation and transcription activation”

Mediator is a eukaryotic complex composed of 25 to 30 subunits which is essential for activated transcription of all RNA Polymerase II (Pol II) genes. Mediator is recruited by transcription activators and then stimulates the assembly of the general transcription factors (GTFs) and Pol II on promoters to form pre initiation complex formation (PIC) and activate transcription.

We have investigated the mechanisms by which Mediator stimulates the assembly of PIC using approaches that range from genetics, biochemistry, mass spectrometry, functional genetics and bioinformatics. We concentrated on the role of protein-protein interaction and showed that Mediator plays key roles in the assembly of TFIIH, TFIIB, TBP and Pol II. We also discovered that contrary to the standard model of transcription activation derived from biochemical experiments, the assembly of the GTFs does not follow an single linear pathway but that alternative pathways can used depending on the promoter. Finally, we also showed that the consequence of mutations affecting the middle module has different consequences depending on the promoter organization and chromatin structure suggesting a link between nucleosome positioning and PIC formation.


Invitation : Andreas Bikfalvi – Inserm U 1029

Vendredi 20 mai 2016 à 14 h 00
Salle de conférences de l’IBGC

Curzio Ruegg
Université de Fribourg – Suisse – Tumor Microenvironement Biology.

A new model of spontaneous breast cancer metastasis to the brain.”

Brain metastases occur in about 25% of patients with disseminated breast cancer. The poor prognosis and short median survival time (80% mortality within one year) mirror the lack of effective therapies. We developed a novel model of spontaneous (4T1-BM2) breast cancer metastasis to the brain in immunocompetent mice. Employing functional investigations and gene expression analysis on this model, coupled with clinical transcriptomic and histopathological analyses, we identified several candidate molecules mediating brain metastasis and correlating with shorter brain metastasis-free survival in breast cancer patient datasets. From the characterization of these molecules it emerges that the most critical step of brain metastasis identified in this model is the colonization of the brain parenchyma.


Invitation : Muriel Cario-Andre – Inserm U 1035

Jeudi 19 mai 2016 à 11 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Masaharu TAKIGAWA
Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine,
Dentistry and Pharmaceutical Sciences
2-5-1 Shikata-cho, Kita-ku, Okayama 700- 8525, Japan
E-mail: takigawa@md.okayama-u.ac.jp.

“Roles of CCN proteins in skeletal growth, homeostasis and regeneration”

We have shown that CCN family member 2 (CCN2), also known as connective tissue growth factor (CTGF), is an endochondral ossification genetic factor that has been termed “ecogenin”, because in vitro studies revealed that CCN2 promotes the proliferation and differentiation of growth-plate chondrocytes, osteoblasts, vascular endothelial cells and osteoclast precursor cells, all of which play important roles in endochondral ossification. For confirmation of this “ecogenin” hypothesis, transgenic mice over-expressing CCN2 in cartilage were generated. The results proved the hypothesis; i.e., the over-expression of CCN2 in cartilage stimulated the proliferation and differentiation of growth-plate chondrocytes, resulting in the promotion of endochondral ossification. In addition to its “ecogenin” action, CCN2 had earlier been shown to promote the differentiation of various cartilage cells including articular cartilage cells. In accordance with these findings, cartilage-specific overexpression of CCN2 in the transgenic mice was shown to protect against the development of osteoarthritic changes in aging articular cartilage. Thus, CCN2 may also play a role as an anti-aging (chondroprotective) factor, stabilizing articular cartilage.
For future clinical application, it is important to discover a more robust and effective CCN2 derivative to induce regeneration because it is difficult to prepare large amount of stably active full length CCN2. Therefore, we next investigated the effects of the 4 modules composing CCN protein independently and their combinations on chondrocytic cells in vitro and damaged cartilage in vivo, especially in relation to full length CCN2. Interestingly, combination of all 4 modules redeemed the effect of intact CCN2 in vivo. Next, the thrombospondin 1 type 1 repeat module (TSP1), which was found most promising in the experiments in vitro, and the combination of 4 modules were forwarded further to in vivo confirmation using 2 rat osteoarthritis (OA) models. As a result, TSP1 modules displayed more prominent regenerative effects than intact CCN2 on damaged cartilage. Unexpectedly, the combination of 4 modules showed limited effects in vivo. These results indicate the utility of TSP1 in the regenerative therapeutics of OA.
Another approach to target CCN2 for OA therapy is up-regulation of gene expression of CCN2 in articular cartilage. As a non-invasive treatment, we chose low-intensity pulsed ultrasound (LIPUS). LIPUS treatment promoted gene expression and protein production of CCN2 and expression of aggrecan and collagen type II, which are two major cartilage matrix components, in cultured normal chondrocytes, but not those in ccn2-deficint chondrocytes. LIPUS treatment also stimulated gene expression of CCN2 in articular cartilage in vivo, strongly suggesting that the treatment is useful for OA therapy.
In addition to CCN2, CCN3 is also important for homeostasis of articular cartilage. We recently discovered that CCN3 is expressed by articular chondrocytes in normal rat knee, whereas it is rapidly down-regulated in osteoarthritic knees. In vitro, exogenous CCN3 increased the proteoglycan accumulation, the gene expression of type II collagen, tenascin-C and lubricin, as well as the protein production of tenascin-C and lubricin in articular chondrocytes. Administration of CCN3 into joint cavity in rat monoiodoacetate (MA)-induced OA model maintained tidemark integrity and lubricin-covered smooth surface of articular cartilage. The potential utility and precautions of CCN2 and CCN3 as future therapeutic agents and possible strategies to improve their therapeutic functions are also discussed.


Invitation : Majid Khatib – Inserm U 1029

Mardi 17 mai 2016 à 11 h 00
Salle de conférences de l’IBGC

Gilles Pages
IRCAN Nice – INSTITUT DE RECHERCHE SUR LE CANCER ET LE VIEILLISSEMENT, NICE
CNRS UMR 7284 – INSERM U 1081 – UNS
Team « Normal and pathological angiogenesis »

“Mécanisme de résistance aux traitements anti-angiogéniques dans le cancer du rein : mise en évidence de nouvelles cibles thérapeutiques”

Les cancers du rein sont des tumeurs richement vascularisées. Ils représentent un paradigme pour l’utilisation de traitements anti-angiogéniques ciblant la voie du VEGF et de ses récepteurs. Malgré un effet indéniable de ces traitements sur le prolongement de la survie sans progression des patients, ces thérapies ne sont pas curatives avec des rechutes inéluctables. Identifier les acteurs impliqués dans cette rechute est primordial pour améliorer la prise en charge des patients et pour rationaliser les dépenses de santéNous avons mis en évidence des cytokines pro-angiogéniques/pro-inflammatoires des la famille des cytokines ELR+CXCL (membre fondateur CXCL8/Interleukine 8) qui sont des marqueurs pronostiques d’agressivité tumorale. Ces cytokines s’avèrent être des cibles thérapeutiques pertinentes dans des expériences de tumeurs expérimentales chez la souris. Elles sont également des marqueurs prédictifs de sensibilité aux traitements par sunitinib, le traitement de référence des cancers du rein métastatiques.Nous avons mis en évidence également un mécanisme original de résistance aux traitement par sunitinib lié à sa capacité de séquestration dans les lysosomes et son efflux hors de la cellule. La séquestration cellulaire inhibe le flux autophagique et rend la cellule dépendante du protéasome pour la dégradation des organelles cellulaires déficients ou des protéines dont la conformation est anormale. Ainsi, la combinaison du sunitinib avec des agents déstabilisant les lysosomes, des inhibiteurs de pompes à efflux ou des inhibiteurs du protéasome entraine la mort de cellules résistantes à la drogue.Ce travail pose les bases de futurs essais cliniques avec ces combinaisons de drogues dont l’autorisation de mise sur le marché a été obtenue pour d’autres cancers ou pour l’utilisation de nouveaux anticorps thérapeutiques en cours d’humanisation.


Invitation : Majid Khatib – Inserm U 1029

Mardi 10 mai 2016 à 11 h 00
Salle de conférences de l’IBGC

Bruno Villoutreix
Unit U973 MTi-Bioinformatics
INSERM – University Paris Diderot

“Recherche de sondes chimiques en associant le criblage in silico et in vitro: nouveaux mécanismes et nouvelles cibles ?”

Les approches dites « in silico » combinées de manière rationnelle au travail expérimental à la paillasse permettent de mieux comprendre l’action des substances médicinales et d’en inventer de nouvelles, elles facilitent également l’étude de certains mécanismes physiopathologiques ou encore la recherche de nouvelles cibles thérapeutiques potentielles. Ces technologies et les concepts scientifiques associés aident à faire diminuer sensiblement la part du hasard dans le processus de recherche de nouvelles molécules bioactives et contribuent à diminuer les coûts. Dans ce séminaire, je vais présenter plusieurs approches in silico et montrer qu’en combinant la bioinformatique structurale, le criblage virtuel à haut débit et le criblage expérimental, il a été possible d’identifier des petites molécules qui agissent sur des nouvelles cibles et sur certains mécanismes moléculaires et modules structuraux encore assez peu explorés avec des sondes chimiques.


Invitation : Christophe Grosset – Inserm U 1035 – MIRCADE

Mardi 3 mai 2016 à 11 h 00
Salle de conférences de l’IBGC

Angélique Gougelet
INSERM U1016 Equipe “Oncogenèse des épithelia digestifs”
Institut Cochin – Paris

“miRNAs as promising biomarkers for the treatment and the diagnosis of liver tumours with β-catenin mutations”

Hepatocellular carcinoma (HCC) is the most prevailing primitive tumor of liver, in which around a third of tumors present activating mutations in the β-catenin gene. To better understand liver tumorigenesis dependent on β-catenin, our team created an inducible transgenic mice exhibiting an overactivation of β-catenin signaling following the deletion of its inhibitor Apc. According to the dose of tamoxifen injected to mice, we could either obtain a pretumoral or a tumoral model, mimicking very closely human HCC. Although the molecular pathogenesis of HCC has been well deciphered, its mortality has not been reduced these last years, supporting the need of new therapeutic approaches and better diagnosis tools, i.e. based on microRNAs. Recently, we showed that the targeting of miR-34a with a locked nucleic acid (LNA), could be a potent strategy for HCC mutated for β-catenin. In particular, we showed that the LNA-34a was able to halve Apc-/- tumor progression, consequently to apoptosis and HNF-4α re-expression (Gougelet et al., 2015). We now would like to determine if the targeting of more than 50 microRNAs produced from the imprinted DLK1/Dio3 locus, and induced following β-catenin activation, could be of therapeutic benefit for this type of tumours. In fact, we observed that all the members of the DLK1/Dio3 locus are upregulated following β-catenin activation in the pretumoral model: the 54 miRNAs (including miR-136), the long non-coding RNA MEG3, and also coding RNAs like Rtl1 and DLK1, either expressed from maternal or paternal strands. This suggests that parental imprinting is lost following β-catenin activation. In ChIP experiments, we identified a binding site for TCF-4/β-catenin upstream the locus, presuming a potential direct control by β-catenin. Interestingly, we confirmed these results in human and mouse HCC activated for β-catenin. However, the locus expression is weaker than those observed in the pretumoral model, suggesting that the deregulation of the locus might be an early consequence of β-catenin activation. This was confirmed using hepatocyte sorting following β-catenin activation with an adenovirus Cre-GFP. The DLK1/Dio3 locus is also regulated by methylation processes as highlighted by our experiments performed on primary culture of hepatocytes using two demethylating agents, the global drug 5-azacytidine and ascorbic acid, a more locus-specific agent. As expected, both agents induced the locus expression in control hepatocytes, but, strikingly, inversely repressed its expression in Apc-/- hepatocytes. Additionally, 5-azacytidine treatment, as well as the silencing of MEG3, a member of the locus, both limit hepatocyte proliferation. It thus appears that a control of the DLK1/Dio3 locus expression in hepatocytes with β-catenin oncogenic activation could be a promising strategy to block their pro-tumoral fate, but could also constitute interesting diagnosis biomarkers since its expression is early modified following β-catenin activation.


Invitation : Jean Rosenbaum – Inserm U 1053

Jeudi 21 avril 2016 à 11 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Jean-Sébastien Annicotte
UMR 8199 (CNRS / Université de Lille 2 / Institut Pasteur de Lille)
Génomique Intégrative et Modélisation des Maladies Métaboliques
Integrative Genomics and Modelling of Metabolic Diseases.

FR 3508 (CNRS / Université de Lille 2 / Institut Pasteur de Lille / CHRU)
Institut Européen de Génomique du Diabète – E.G.I.D
European Genomics Institute of Diabetes.

“E2F1, cell cycle and metabolic homeostasis: One for all, all for one”

Obesity is predicted to affect more than one billion people by 2030 and represents a major risk factor for several obesity-related diseases such as type 2 diabetes (T2D), cardiovascular diseases and some cancers. We previously evaluated the role of several cell cycle regulators in the control of energy metabolism and diet-induced obesity (Lopez-Mejia and Fajas, 2015). We demonstrated that the CDK4-E2F1-pRb pathway, previously shown to control tumor progression, is involved in the control of diet-induced obesity through the control of insulin secretion and action, lipogenesis, mitochondrial activity and global energy expenditure in adipose tissue and muscle. Interestingly, early studies by Warburg (Warburg, 1956) found that, during the process of tumorigenesis, cells need to obtain nutrients and metabolize glucose for their rapid growth. The control of glucose and lipid homeostasis by these cell cycle regulators might represent a potential link between metabolic homeostasis and cancer progression.


Invitation : Harry Wodrich – CNRS UMR 5234

Mercredi 20 avril 2016 à 11 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Ralph Kehlenbach
Georg-August-Universität Universitätsmedizin Göttingen
Zentrum Biochemie und Molekulare Zellbiologie
Institut für Molekularbiologie

“Transport of proteins to the inner nuclear membrane”

The inner nuclear membrane harbors a set of distinct proteins that are enriched at this positions. Very little is known, however, about the molecular mechanisms of protein targeting to the inner nuclear membrane. Proteins could reach their final destination by passive diffusion, followed by retention to a binding partner at the nuclear side of the nuclear envelope. Alternatively, proteins could be actively transported across the nuclear pore complex in a receptor-dependent manner, similar to soluble proteins. In my talk I will present examples of proteins that follow either pathway.


Invitation : Julie Dechanet-Merville – CNRS UMR 5164 – ALYSAI

Jeudi 14 avril 2016 à 11 h 00
Salle de conférences de l’IBGC

Dorothée Duluc
Maître de Conférence – Alysai – CNRS UMR 5164

“Analysis of immune cells in tumor microenvironment: focus on myeloid cells and development
of novel immunotherapy approaches.”

Despite major therapeutic advances, cancer remains a leading cause of death, in part due to the acquisition of resistance of certain tumors to conventional treatments. These difficulties warrant the development of novel therapeutic approaches such as immunotherapy, which is based on the ability of cells and / or mediators of the immune system to destroy tumor cells. I will be talking about my past work in the field of tumor immunology and immunotherapy and then present scientific projects that will be developed in Bordeaux. First, dendritic cells are immune cells essential for the initiation of effective anti-tumor responses. Thus, they represent a primary target for immunotherapy. In my postdoctoral laboratory, we developed therapeutic vaccine approaches targeting dendritic cells in vivo (called “DC-targeting”). Several parameters must be taken into account for the design of this type of vaccine. The targeted population of dendritic cells and the receptor through which the cell is targeted are essential, as they may determine the type of immune response. My work focused on determining the populations of dendritic cells of the vaginal mucosa and to test a prototype vaccine targeting dendritic cells for the induction of anti-human papilloma virus (HPV) responses, a causative agent of cervical cancer and some oropharyngeal cancers. Second, the effectiveness of anti-tumor immunotherapy approaches relies on the ability to overcome local immunosuppression mediated by various immune cells including tumor-associated macrophages (or TAM). TAM differentiate from circulating monocytes. We have identified soluble factors from the tumor environment involved in the differentiation of these macrophages in ovarian cancer and then identified IFNg as a promising candidate to overcome part of the tumor-associated immunosuppression. Finally, I will present the research project that we are developing in Bordeaux on the immune cells in the tumor environment of chronic lymphocytic leukemia.


Invitation : Nicolas Larmonier- CNRS UMR 5164 – ALYSAI

Jeudi 7 avril 2016 à 11 h 00
Salle de conférences de l’IBGC

Pr. Emmanuel Katsanis
MD (Professeur Hématologie/Oncologie/BMT/Immunobiologie) de l’Université d’Arizona (USA)

“Should post-transplant cyclophosphamide be the standard of care in haploidentical bone marrow transplantation?”


Invitation : Frédéric Bringaud – CNRS UMR 5234 et Christophe Grosset – Mircade Inserm U 1035

Mardi 22 mars 2016 à 11 h 00
Salle de conférences de l’IBGC

Daniel Compagno
MOLECULAR and FUNCTIONAL GLYCO-ONCOLOGY Lab
IQUIBICEN-CONICET – Facultad de Ciencias Exactas y Naturales-Universidad de Buenos Aires – Argentina

“Influence des galectines au cours de la progression du cancer de la prostate.”

Le Cancer de la Prostate (CaP) est un problème majeur de santé publique en France et à travers le monde. L’association des traitements de radiothérapie, de chirurgie et d’ablation androgéniques sont seulement efficaces dans les cas de tumeurs de la prostate localisées. Cependant, 15 à 20% des patients évoluent vers des stades avancés de la pathologie par le développement de métastases osseuses et dans les ganglions lymphatiques des patients, pour lesquels il n’y a pas à l’heure actuelle de traitements adéquats et efficaces.
Le processus métastatique est composé de plusieurs étapes impliquant non seulement la cellule tumorale mais aussi les composants du microenvironnement qui l’entoure. Il est démontré dans d’autres cancers que la reconnaissance de glycoconjugués par Galectines (Gal-), une famille de lectines animales, joue un rôle fondamental dans la propagation métastatique, les processus de tolérance ou privilège immunitaire et pour une néovascularisation indispensable au développement tumoral. Les Gal participent activement aux processus intrinsèques des cellules tumorales, ainsi qu’au sein du tissu stromal, endothéliale et du système immunitaire. Malgré leur expression ubiquitaire, les Gal ont des fonctions particulières qui peuvent variées d’un cancer à l’autre, comme nous l’avons montré par exemple récemment pour Gal-1 : protéine indispensable à la néovascularisation du cancer de la prostate mais pas de celle du cancer du sein expliquant ainsi l’échec des thérapies anti-angiogéniques par l’Avastin chez les patients avec un CaP.

L’objectif principal de notre projet était ensuite de comprendre le rôle de Gal-3 et Gal-8 dans la progression du CaP : de la mise en place de la tumeur primaire (stade précoce de la maladie avec une tumeur localisée) jusqu’à un stade avancé avec propagation tumorale et apparition spontanée de métastases.
Pour cela, nous avons tout d’abord développé un nouveau modèle préclinique murin du CaP qui nous permet d’étudier toutes les étapes de la progression tumorale.
Nous avons ainsi démontré que Gal-3 produite par les cellules tumorales est essentielle à l’établissement d’un microenvironnement tolérogène, affectant la prolifération, l’activation et la cytotoxicité des cellules T CD8 +. De cette manière, nous montrons le rôle de Gal-3 dans différents paramètres-clés impliqués dans le développement du CaP et proposons cette galectine comme une nouvelle cible moléculaire pour l’amélioration des protocoles thérapeutiques actuels.
Aussi, nous avons évalué le rôle de Gal-8 dans la progression de cette maladie. Nos résultats montrent que Gal-8 est exprimée à partir des stades précoces du CaP, et permet l’apparition de métastases. De la même manière que pour Gal-3, le contrôle de l’expression de Gal-8 par ARN interférence révèle pour la première fois que cette galectine est exprimée fortement et de manière stable tout au long de la maladie et est responsable du processus métastatique du CaP.
Nos données pourraient apporter des informations importantes quant au développement de métastases de ce type de cancer, étape pour laquelle le patient a très peu de chance de survie, et de proposer de nouvelles stratégies thérapeutiques ciblant ces galectines afin d’empêcher la dissémination des cellules de CaP et d’améliorer les chances de survie des patients.


In
vitation : Bertrand Daignan-Fornier – IBGC CNRS UMR 5095

Jeudi 17 mars 2016 à 11 h 00
Salle de conférences de l’IBGC

Arnaud Mourier
CNRS-CR1
I.B.G.C (UMR5095)
– Bordeaux

“Analyse du métabolisme énergétique mitochondrial chez les souris transgéniques modèles de la neuropathie mitochondriale
de Charcot Marie Tooth de type 2A.”.

Les maladies de charcot-Marie-Tooth (CMT) sont des maladies génétiques héréditaires affectant environ 30 000 personnes en France. La variante CMT-2A est une neuropathie axonale affectant les nerfs périphériques qui est liée à une perte de fonction de la protéine mitochondriale mitofusin 2 (MFN2). MFN2 est localisée au niveau de la membrane externe mitochondriale et contrôle la fusion mitochondriale. Jusqu’alors le rôle exact de MFN2 dans le maintien des fonctions mitochondriales et dans le fonctionnement des nerfs périphériques reste énigmatique empêchant ainsi le développement de traitements adaptés. Mon travail postdoctoral a permis, via la caractérisation de souris transgéniques, de comprendre l’importance fonctionnelle jouée par Mitofusin 2 dans le métabolisme énergétique mitochondrial cardiaque. L’implication de cette protéine dans le maintien de la voie de biosynthèse des mévalonates représente un nouveau mécanisme physio-pathologique de régulation du métabolisme mitochondrial et pourrait aussi constituer une cible thérapeutique pour la maladie de CMT-2A.


Invitation : Nadine Camougrand – IBGC CNRS UMR 5095

Jeudi 11 février 2016 à 11 h 00
Salle de conférences de l’IGBC

Renaud Legouis
I2BC – Institut de Biologie Intégrative de la Cellule – Gyf-sur-Yvette

Autophagy and Development :Lessons from C. elegans”.

For a long time, autophagy has been mainly studied in yeast or mammalian cell lines, but more recently, the involvement of autophagy in various physiological functions has been investigated in multicellular organisms. Modification of autophagy flux is involved in developmental processes, resistance to stress conditions, aging, cell death and multiple pathologies. So, the use of animal models is essential to understand these processes in the context of different cell types and during the whole life. For ten years, the nematode Caenorhabditis elegans has emerged as a powerful model to analyze autophagy in physiological or pathological contexts. I’ll present some of our recent works concerning the functions of the LC3 ubiquitin-like family during development and particularly during selective mitophagy.

Manil-Ségalen M, Lefebvre C, Jenzer C, Trichet M, Boulogne C, Satiat-Jeunemaitre B, Legouis R. The C. elegans LC3 Acts Downstream of GABARAP to Degrade Autophagosomes by Interacting with the HOPS Subunit VPS39. Dev Cell. 2014 28(1):43-55.
Jenzer C, Manil-Ségalen M, Lefebvre C, Largeau C, Glatigny A, Legouis R. Human GABARAP can restore autophagosome biogenesis in a C. elegans lgg-1 mutant. Autophagy 2014 Oct 1;10(10):1868-72.
Al Rawi S, Louvet-Vallée S, Djeddi A, Sachse M, Culetto E, Hajjar C, Boyd L, Legouis R*, Galy V*. Postfertilization autophagy of sperm organelles prevents paternal mitochondrial DNA transmission. Science. 2011 334(6059):1144-7.* Last authors
Alberti A, Michelet X, Djeddi A, Legouis R. The autophagosomal protein LGG-2 acts synergistically with LGG-1 in dauer formation and longevity in C. elegans. Autophagy. 2010 6(5):622-33.


Invitation : Muriel Priault – IBGC CNRS UMR 5095

Jeudi 4 février 2016 à 11 h 00
Salle de conférences de l’IBGC

Germain Gillet

“Bcl-2 proteins and calcium trafficking: lessons from zebrafish”.

We previously showed that vertebrate cells transformed by the v-src oncogene are resistant to numerous apoptotic stimuli, including heat shock and serum withdrawal, at least in part as a consequence of nr-13 overepression, a bcl-2 homologue with anti-death activity. However, the Bcl-2 family of apoptosis regulators, including Nr-13 and the zebrafish homolog Nrz, seem to play other roles that are not directly related to the control of cell death. We are currently studying the signaling pathways that are deregulated in nrz-deficient zebrafish embryos. The knock down of nrz results in developmental arrest before gastrulation, due to free Ca2+ increase in the yolk cell, leading to the activation of the myosin light chain kinase and subsequent separation of the blastomeres from the yolk cell (1,2). Nrz was found to prevent the release of Ca2+ from the endoplasmic reticulum by directly interacting with the IP3R1 Ca2+ channel. Thus, the Bcl-2 family appears to participate in early development, not only by controlling apoptosis but also by acting on cytoskeletal dynamics and cell movements via Ca2+ fluxes inside the embryo. These studies may shed new light on the role of cell death regulators during the early steps of vertebrate development and have implications in the understanding of morphogenetic movements during gastrulation. Together our results may also contribute to a better understanding of the molecular mechanisms underlying metastasis formation.
(1) Popgeorgiev et al «The apoptotic regulator Nrz controls cytoskeletal dynamics via the regulation of Ca2+ trafficking in the zebrafish blastula » (2011) Developmental Cell
(2) Bonneau et al «The Bcl-2 Homolog Nrz Inhibits Binding of IP3 to Its Receptor to Control Calcium Signaling During Zebrafish Epiboly » (2014) Science Signaling


Invitation : Isabelle Sagot – IBGC CNRS UMR 5095

Jeudi 28 janvier 2016 à 11 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Zuzana Storchova
Maintenance of Genome Stability
MPI of Biochemistry, Martinsried

“From Down’s syndrome to cancer: how aneuploidy affects eukaryotic cells”.

Eukaryotic organisms are mostly diploid, containing two sets of chromosomes, yet exceptions can be found. Aneuploidy describes a situation when cells contain unbalanced number of chromsomes: some got an extra chromosome or two, some might have lost a chromosome arm. These alterations are rather rare in normal, healthy organisms, but often they are found under pathological conditions, such as trisomy syndromes or cancer. Recent analysis of model cells with defined aneuploid karyotypes shed new light on the consequences of aneuploidy. In this talk, novel findings from aneuploid human cells will be presented, with a focus on changes in gene expression, protein homeostasis and genomic stability in response to aneuploidy.


Invitation : Julie Dechanet-Merville – ALYSAI CNRS UMR 5164

Mercredi 27 janvier 2016 à 14 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Martin Larsen
Centre d’Immunologie et des Maladies Infectieuses (CIMI Paris), Inserm UMR-S1135, Paris, France

“Gut microbiota and host immunity in multiple sclerosis.”

Man has developed spectacular ways to protect himself from pathogens, while benefitting from unique and essential features of symbionts. Symbionts not only play for us essential metabolic roles but also shape our immune system. Our preliminary data show that human gut and systemic antibody responses target a restricted fraction of gut commensals. We postulate that commensals preferentially targeted by adaptive humoral immunity are of particular importance for host immunity and autoimmunity. Multiple sclerosis (MS) is a human autoimmune disease triggered by host genetics and environmental factors. A recent mouse study suggests that the gut microbiota is a strong environmental trigger of MS. Combining state-of-the-art immune-technologies and large-scale metagenomic analysis we have successfully identified immune-reactive gut commensals targeted by gut and systemic host immunoglobulins in healthy individuals and MS patients. Our preliminary data suggest that the immune-reactive gut microbiota is skewed in MS patients and that it contains bacterial species endowed with properties making them important candidates for immune diagnostics and therapy of multiple sclerosis.


Invitation : Julie Dechanet-Merville – ALYSAI CNRS UMR 5164


Mardi 19 janvier 2016 à 11 h 00

Salle de conférences de la Plateforme Génomique Fonctionnelle

Carlos Vilches
Inmunogenética – HLA
Hospital Univ. Puerta de Hierro – Madrid, Spain

“Epigenetics and regulation of immune cells: example of KIR2DL5, an orphan receptor with complex genetics and expression profiles”.


Invitation : Christophe Richez et Patrick Blanco – CNRS UMR 5164

Jeudi 14 janvier 2016 à 11 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Bernard R. Lauwerys
Pôle de pathologies rhumatismales inflammatoires et systémiques, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium

“Pathogenesis of systemic lupus erythematosus : distinct mechanisms drive systemic versus local disease activity”

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by a break of tolerance to chromatin, and the development of antinuclear antibodies. Due to the presence of genetic susceptibility factors, SLE patients produce larger amounts and/or respond better to interferon (IFN)-alpha, and the stimulatory role of this cytokine on antigen-presenting and autoreactive CD4 T cells was well documented. Based on ex vivo data from SLE patients treated with IFN kinoid, an IFN-alpha blocking agent, and further in vitro experiments, we also found evidence that the cytokine plays a direct role on the skewed B cell differentiation pattern observed in the disease (i.e. differentiation of naive and unswitched memory B cells into switched memory, double negative B cells and plasmablasts), thereby emphasizing the pathogenic role of IFN-alpha in SLE.

Intriguingly, our ex vivo observations allowed us to understand how distinct mechanisms drive systemic (i.e. autoantibody production) versus local disease activity in SLE. Thus, we could document the presence of a TLR3 / IFN-beta stimulation axis in SLE skin samples, and showed how TLR3 mediates the priming effects of UV irradiation on dendritic cells, and stimulation of autoreactive T cells in vitro. Our current work focuses on the lupus kidney, in which the first wave (autoantibody deposition) is followed by a second wave of immune effectors, which seems to play a predominant role on local disease outcomes, independently of systemic disease activity.


Invitation : Harald Wodrich – CNRS UMR 5234

Mardi 12 janvier 2016 à 11 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Tassula Proikas-Cezanne
Eberhard Karls University Tübingen – Germany
Interfaculty Institute of Cell Biology · Department of Molecular Biology

“Control of autophagy through differential PI(3)P-effector functions of human WIPI proteins”.

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