Inflammation, the first immune response to infection or tissue injury, is crucial for host survival, but can also be a maladaptive response at the origin of many diseases when chronically activated. Recent evidences indicate that accumulation of unfolded proteins in the ER may act as a “anger”signal that participates in the inflammatory response by activating ER-associated receptors (IRE1, ATF6 and PERK) signaling pathways leading to pro-inflammatory cytokine production and/or cell death. This research project aims to identify the cellular pathways and molecular mechanisms regulating IRE1’ functions, in the hope to define ways to modulate ER stressinduced inflammation. To reach our goals, we will develop two parallel approaches. In the first one, the hypothesis-driven approach, we will study the role of nondegradative ubiquitination (through the analyses of RIP1, TRAF2 and cIAP1/2 proteins) in the IRE1’ pathways. In the second one, the non-biased one, we will perform genome wide screens to identify novel modulators of IRE1 signaling pathways. Our finding will then be tested in vivo, using a mouse model of colitis that has been shown to depend on IRE1’ functions.