THESIS DEFENSE

Simon LE GOUPIL

PhD candidate in UMR INSERM U1242 Oncogenesis Stress Signaling

PROSAC Team

Abstract:
The unfolded protein response (UPR) is a key mechanism that primarily aims to restore endoplasmic reticulum (ER) homeostasis and is likely involved in other adaptive pathways of particular relevance to cancer. The UPR is transduced by three proteins acting as sensors and triggering signaling pathways. Among them, IRE1α, an ER-resident type I transmembrane protein, exerts its function through both kinase and endoribonuclease activities that result in both XBP1 splicing and RNA cleavage (Regulated IRE1 Dependent Decay - RIDD) through mechanisms that remain to be clearly documented. Recently an increasing number of studies have reported that protein-protein interactions (PPi) regulate IRE1α signaling, and can drive additional non-canonical functions associated with this protein. Here, we developed a BioID-based approach in HEK293T cells aiming to label proteins in proximity of IRE1α in situ. The resulting IRE1α interactome identified 207 proteins, of which 25% appear during ER stress. We further define the IRE1α signalosome (i.e. proteins in complex with IRE1α that affect signaling properties of the protein) based on literature, computational analyses and subsequent experiments, allowing us to document how PPi may regulate the IRE1α pathway and associated biological outcomes. Furthermore, we elaborate on potentially novel IRE1α functions based on the nature of its interactors and their localization.