Epithelial cells which cover external and internal surfaces of the body and of all organs perform essential functions such as barrier, absorption, filtration or respiration. These functions requires the establishment and the maintenance of a cell polarity specific to epithelial cells. Using C. elegans our team seeks to identify and characterise the key factors essential for the maintenance of epithelial polarity in two contexts:
- how membrane traffic controls epithelial polarity and food absorption in the intestine.
- how a biomechanical signaling pathway controls embryonic morphogenesis.
Le fonctionnement des systèmes nerveux et neuroendocrine repose sur une communication cellulaire élaborée assurée par un intense trafic membranaire (exocytose, endocytose, autophagie, phagocytose). Le but de nos recherches est d’en décrypter les mécanismes moléculaires dont l’altération est à la base de pathologies (maladies neurodégénératives, retard mental, cancers neuroendocrines). Pour cela nous étudions spécifiquement le rôle des protéines d’arrimage et de fusion membranaire, ainsi que la formation des domaines lipidiques et l’organisation du cytosquelette.
Ubiquitylation is a rapid, reversible and versatile post-translational modification, directing proteins to a myriad of fates. A key regulatory step of the ubiquitylation cascade is dictated by the E3 ubiquitin ligase which confers substrate selectivity. The reversibility of this post-translational modification is driven by deubiquitinating enzymes responsible for removing ubiquitin conjugates from substrates. While best known for targeting proteins to proteasomal degradation, ubiquitylation is also used for proteolytic-independent functions. Of note, alteration of the ubiquitin pathway results in human disease pathogenesis including cancer, muscle disorders or inflammatory and infectious diseases. Importantly, components of the ubiquitin system are amenable to pharmacological manipulation.
A main objective of our team is to decipher the roles of the ASB2 E3 ubiquitin ligases in physiological and pathological settings using state-of-the-art mouse mutant models as well as cellular and molecular approaches. The ASB2 gene encodes two protein isoforms, ASB2α and ASB2β, that are the specificity subunits of Cullin 5-RING E3 ubiquitin ligases suggesting that ASB2 proteins exert their effects through the targeting of specific substrates for degradation by the proteasome. Investigating ASB2-ASB2 substrate axes will provide important mechanistic insights into the contribution of the ubiquitin pathway to major biological functions that could be exploited in therapeutic purposes.