RT Journal Article
SR Electronic
T1 OTUD1 deubiquitylase regulates NF-κB- and KEAP1-mediated inflammatory responses and reactive oxygen species-associated cell death pathways
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.12.26.474226
DO 10.1101/2021.12.26.474226
A1 Oikawa, Daisuke
A1 Gi, Min
A1 Kosako, Hidetaka
A1 Shimizu, Kouhei
A1 Takahashi, Hirotaka
A1 Shiota, Masayuki
A1 Hosomi, Shuhei
A1 Komakura, Keidai
A1 Wanibuchi, Hideki
A1 Tsuruta, Daisuke
A1 Sawasaki, Tatsuya
A1 Tokunaga, Fuminori
YR 2021
UL http://biorxiv.org/content/early/2021/12/27/2021.12.26.474226.abstract
AB Deubiquitylating 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-κB activation, and identified OTUD1 as a potent suppressor. OTUD1 regulates the canonical NF-κB pathway by hydrolysing K63-linked ubiquitin chains from NF-κB signalling factors, including LUBAC. OTUD1 negatively regulates the canonical NF-κB activation, apoptosis, and necroptosis, whereas OTUD1 upregulates the interferon (IFN) antiviral pathway. The N-terminal intrinsically disordered region of OTUD1, which contains an EGTE motif, is indispensable for KEAP1-binding and NF-κB suppression. 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.Competing Interest StatementThe authors have declared no competing interest.