OTUD1 deubiquitinase regulates NF-?B- and KEAP1-mediated inflammatory responses and reactive oxygen species-associated cell death pathways.

Deubiquitinating enzymes (DUBs) regulate numerous cellular functions by removing ubiquitin modifications. We examined the effects of 88 human DUBs on linear ubiquitin chain assembly complex (LUBAC)-induced NF-?B activation, and identified OTUD1 as a potent suppressor. OTUD1 regulates the canonical NF-?B pathway by hydrolyzing K63-linked ubiquitin chains from NF-?B signaling factors, ...
including LUBAC. OTUD1 negatively regulates the canonical NF-?B activation, apoptosis, and necroptosis, whereas OTUD1 upregulates the interferon (IFN) antiviral pathway. Mass spectrometric analysis showed that OTUD1 binds KEAP1, and the N-terminal intrinsically disordered region of OTUD1, which contains an ETGE motif, is indispensable for the KEAP1-binding. Indeed, OTUD1 is involved in the KEAP1-mediated antioxidant response and reactive oxygen species (ROS)-induced cell death, oxeiptosis. In Otud1-/--mice, inflammation, oxidative damage, and cell death were enhanced in inflammatory bowel disease, acute hepatitis, and sepsis models. Thus, OTUD1 is a crucial regulator for the inflammatory, innate immune, and oxidative stress responses and ROS-associated cell death pathways.
Mesh Terms:
Animals, Cell Death, Deubiquitinating Enzymes, Humans, Kelch-Like ECH-Associated Protein 1, Mice, NF-E2-Related Factor 2, NF-kappa B, Reactive Oxygen Species, Ubiquitin, Ubiquitin-Specific Proteases, Ubiquitination
Cell Death Dis
Date: Aug. 08, 2022
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