Impact of autophagy on intestinal homeostasis
Autophagy dysfunctions have been implicated in inflammatory bowel diseases (IBD). GWAS studies have identified numerous variants in membrane trafficking or autophagic regulators. How are genetic predispositions inter-twinned with environmental factors, the microbiota and innate immune responses is still poorly understood. Using Drosophila as a simple genetic model and human enteroids to understand how autophagy impairment affects intestinal homeostasis, we hope to be able to better define the importance of genetic factors in IBD.
Endosomal sorting regulation by RAB21
Cell surface transporters, receptors and adhesion molecules undergo basal and stimulated endocytosis. Once internalized, these transmembrane cargoes can either progress towards lysosomal degradation or can be rescued and recycled back to the plasma membrane or the trans-Golgi network. Endosomal recycling is an active process that relies on various protein complexes, which recognize cargos and sequester them into transport intermediate. The WASH complex drives endosomal actin polymerization and is essential to endosomal sorting events. This research program aims to define the molecular regulation of the WASH complex by the small RAB GTPase RAB21. Using unbiased proteomics, we have recently identified RAB21 as a bona fide WASH-associated protein and discovered that RAB21 regulates endosomal actin polymerization. We are now defining how a RAB GTPase coordinates the activity of the WASH complex.
RAB GTPases proximity interactome and links to lipid transfer proteins
RAB GTPases govern trafficking events. They are under the dynamic regulation of GEFs and GAPs, which shape their membrane recruitment. Single RABs can be activated by various stimuli and regulate trafficking differently. However, how RAB GTPases integrate these various stimuli to generate a different response is not well understood. We defined RAB GTPase neighbours in HeLa cells through APEX2-BioID and have validated multiple hits. We are now studying links between a subset of RABs and various lipid transfer proteins in both human cells and genetically in Drosophila.