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

Abstract

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-κB activation, and identified OTUD1 as a potent suppressor. OTUD1 regulates the canonical NF-κB pathway by hydrolyzing K63-linked ubiquitin chains from NF-κB signaling factors, including LUBAC. OTUD1 negatively regulates the canonical NF-κB 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.

Divergent Epigenetic and Transcriptomic Reprogramming of Monocyte Subpopulations in Systemic Lupus Erythematosus

“…Cluster M4 contains 58 DMPs that demethylate in the differentiation from cMOs to ncMOs and that in SLE iMOs are more advanced in the demethylation process than their HD counterparts (Figure 1D,E). Examples of DMPs in the M4 cluster include those annotating to PDE4B , encoding a key element for the monocyte’s response to LPS [38] and PIK3R5 , that encodes a regulatory subunit of PI3K complex, relevant for several immune functions in monocytes including cytokine release and adhesion [39–41] (Figure 1F). The remaining clusters from M5 to M7 (127, 93 and 11 DMPs) were characterized by hypermethylation in SLE in comparison with HD, being the predominant one M5, with similar hypermethylation levels for all monocyte subsets (Supplementary Figure 1A and 1B).…”

“…Cluster M2 (41 DMPs) annotate to genes that have a more drastic hypomethylation in cMOs than in iMOs and ncMOs when comparing HD vs SLE (Figure 1D,E). It is the case of genes like ZMIZ1, a member of the PIAS (protein inhibitor of activated STAT) protein family, and OTUD1, a deubiquitinase related to TNF and IFN signaling [37] (Figure 1F). Cluster M3 (15 DMPs) is particularly interesting as it corresponds to positions hypomethylated in SLE ncMOs in comparison with HD ncMOs (Figure 1D,E).…”

Anti‐inflammatory cerium‐containing nano‐scaled mesoporous bioactive glass for promoting regenerative capability of dental pulp cells

“…Our study simulated the early inflammatory state of innate immune cells and DPCs to undergo respiratory bursts and release ROS. Ce‐MBGNs as pulp‐capping agent can well exert antioxidant effects and protect host cells from self‐generated oxidative damage (Oikawa et al., 2022; Sauer et al., 2001; Westhauser et al., 2020), thereby improving the success rate of pulp‐capping therapy.…”

Involvement of heterologous ubiquitination including linear ubiquitination in Alzheimer’s disease and amyotrophic lateral sclerosis

“…Although A20 cleaves K63- and K48-ubiquitin chains, but not the M1-ubiquitin chain, A20 downregulates LUBAC-induced NF-κB activation by specifically binding to the M1-ubiquitin chain through the zinc finger 7 (ZF7) domain ( Tokunaga et al, 2012 ). In contrast, OTUD1 extensively removes K63-ubiquitin chains in LUBAC and TNF-α receptor complex I, thus regulating the canonical NF-κB, KEAP1-mediated antioxidant response, and reactive oxygen species (ROS)-associated cell death pathways ( Oikawa et al, 2022 ). Collectively, these findings indicate that LUBAC and its related DUBs build and scrap linear ubiquitin chains, and thus participate in various pathophysiological phenomena.…”