Éditeur(s) : HAL CCSD Royal Society
Résumé : International audience
Maternal Embryonic Leucine zipper Kinase (MELK) was recently shown to be involved in cell division of Xenopus embryo epithelial cells. The cytokinetic furrow of these cells ingresses asymmetrically and is developmentally regulated. Two subpopulations of xMELK, the mMELK (for "mitotic" xMELK) and iMELK ("interphase" xMELK), which differ in their spatial and temporal regulation, are detected in Xenopus embryo. How cells regulate these two xMELK populations is unknown. In this study we show that, in epithelial cells, xMELK is present at a higher concentration at the apical junctional complex, in contrast to mesenchyme-like cells, which have uniform distribution of cortical MELK. Interestingly, mMELK and iMELK also differ by their requirements towards cell-cell contacts to establish their proper cortical localization both in epithelial and mesenchyme-like cells. Receptor for Activated protein Kinase C (RACK1), which we identified as an xMELK partner, co-localizes with xMELK at the tight junction. Moreover, a truncated RACK1 construct interferes with iMELK localization at cell-cell contacts. Collectively, our results suggest that iMELK and RACK1 are present in the same complex and that RACK1 is involved in the specific recruitment of iMELK at the apical junctional complex in epithelial cells of Xenopus embryos.
ISSN: 2046-6390

hal-00874053
https://hal.archives-ouvertes.fr/hal-00874053
https://hal.archives-ouvertes.fr/hal-00874053/document
https://hal.archives-ouvertes.fr/hal-00874053/file/Cell-cycle_dependent-accepted.pdf
DOI : 10.1242/bio.20136080

Éditeur(s) : HAL CCSD
Résumé : Communication between tumoral cells and the microenvironnement plays an essential role in the developpement of tumors. In that context, the new family of metalloproteases, the ADAM proteins, are major regulators of the tumoral progression by acting on the bioavaibility of importants mediators of cellular communication as cytokines and growth factors. Among this family, ADAM12 is the most associated with cancer. It has been shown to mediate signaling pathways by a process independant of its metalloproteasis activity, in particular for TGFβ signaling. This study show for the first time a role for the membrane form of ADAM12 in the induction of epithelial to mesenchymal transition (EMT), a essential process involved in tumor invasion, whom TGFβ is a main inducer. This effect is mediated by the activation of TGFβ signaling pathways, SMAD3, AKT and ERK and require the cytoplasmic tail of ADAM12L but not its catalytic activity. Activation of these pathways could involve a relocalisation of ADAM12L in special signaling platform in lipid rafts. Moreover, we have shown that ADAM12L interact with ZO-1 and ZO-2, two proteins of tight junctions, and could facilitate their desassembling during EMT. This work underscore for the first time a new function of ADAM12L in EMT, by a mecanism invovlving a modulation of signals regulating this process. A better understanding of the dynamic of these molecular mecanisms could allow the developpement of new targeted therapies to fight against tumoral progression.
Les échanges entre les cellules tumorales et le microenvironnement jouent un rôle essentiel dans le développement des tumeurs. Dans ce contexte, la nouvelle famille de métalloprotéases, les protéines ADAM, constituent aujourd’hui des régulateurs majeurs de la progression tumorale en agissant sur la biodisponibilité des médiateurs de la communication cellulaire que sont les cytokines, chimiokines et facteurs de croissance. Au sein de cette famille, ADAM12 est la plus associée au cancer. Elle possède la particularité de jouer un rôle dans la signalisation cellulaire, de façon indépendante de son activité métalloprotéase, notamment dans les voies de signalisation du TGFβ. Notre étude montre pour la première fois un rôle pour la forme membranaire d'ADAM12 dans l'induction de la transition épithélio-mésenchymateuse (EMT), un processus essentiel à l'invasion tumorale dont le TGFβ est un inducteur majeur. Cet effet est médié par l'activation des voies de signalisation du TGFβ, impliquant les protéines SMAD3, AKT et ERK et requiert le domaine cytoplasmique d'ADAM12L mais pas son domaine catalytique. L'activation de ces voies de signalisation pourrait impliquer une relocalisation d'ADAM12L au sein de plates-formes de signalisation dans les radeaux lipidiques. Par ailleurs, nous avons montré qu'ADAM12L interagit avec les protéines ZO-1 et ZO-2, des protéines des jonctions serrées, et pourrait favoriser leur désassemblage au cours de l'EMT. Nos travaux ont permis de mettre en évidence une nouvelle fonction pour ADAM12L dans l'EMT, par un mécanisme impliquant une modulation des signaux régulant ce processus. Une meilleure compréhension de la dynamique de ces mécanismes moléculaires pourrait permettre de développer de nouvelles thérapies ciblées pour lutter contre la progression tumorale.
https://tel.archives-ouvertes.fr/tel-01267577

Droits : info:eu-repo/semantics/OpenAccess
NNT : 2015REN1S063
tel-01267577
https://tel.archives-ouvertes.fr/tel-01267577
https://tel.archives-ouvertes.fr/tel-01267577/document
https://tel.archives-ouvertes.fr/tel-01267577/file/RUFF_Michael.pdf

Éditeur(s) : HAL CCSD American Society for Microbiology
Résumé : International audience
Coronaviruses (CoVs) have shown neuroinvasive properties in human and animal secondary to replication in peripheral organ but the mechanism of neuroinvasion is unknown. The major aim of our work was to evaluate the ability of CoVs to enter the central nervous system (CNS) through the blood brain barrier (BBB). Using the high hepatotropic mouse hepatitis virus (MHV) type 3, its attenuated variant 51.6-MHV3, showing low tropism for endothelial cells, and the low hepatotropic MHV-A59 strains from murine coronavirus group, we investigated the viral-induced dysfunctions of BBB in vivo and in brain microvascular endothelial cells (BMECs) in vitro. We report here a MHV strain-specific ability to cross the BBB during acute infection according to their virulence for liver. Brain invasion was only observed in MHV3-infected mice and correlated with enhanced BBB permeability associated with decreased expression of ZO-1, VE-cadherin and occludin but not claudin-5 in the brain or in cultured BMECs. BBB breakdown in MHV3 infection was not related to production of barrier-dysregulating inflammatory cytokines or chemokines by infected BMECs but rather to a downregulation of barrier protective IFN-β production. Our findings highlight the importance of IFN-β production by infected BMECs in preserving BBB function and preventing access of blood-borne infectious viruses to the brain. IMPORTANCE: Coronaviruses (CoVs) infect several mammals including humans and are associated with respiratory, gastrointestinal and/or neurological diseases. Some evidences suggest that human respiratory CoVs may show neuroinvasive properties. Indeed, the SARS-CoV, causing severe acute respiratory syndrome, and the CoVs OC43 and 229E were found in the brains of SARS and multiple sclerosis patients respectively. These finding suggest that hematogenous spread CoVs may gain access to CNS at the BBB level. Herein we report for the first time that CoVs exhibit ability to cross the BBB according to strain virulence. BBB invasion by CoVs correlates with viral-induced disruption of tight junctions on BMECs, leading to BBB dysfunction and enhanced permeability. We provide evidence that production of IFN-β by BMECs during CoV infection may prevent BBB breakdown and brain viral invasion
ISSN: 0022-538X

hal-01187308
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01187308
DOI : 10.1128/JVI.01501-15
PUBMED : 26202229