Pleiotropic Roles of a KEAP1-Associated Deubiquitinase, OTUD1

Abstract

Protein ubiquitination, which is catalyzed by ubiquitin-activating enzymes, ubiquitin-conjugating enzymes, and ubiquitin ligases, is a crucial post-translational modification to regulate numerous cellular functions in a spatio-temporal-specific manner. The human genome encodes ~100 deubiquitinating enzymes (DUBs), which antagonistically regulate the ubiquitin system. OTUD1, an ovarian tumor protease (OTU) family DUB, has an N-terminal-disordered alanine-, proline-, glycine-rich region (APGR), a catalytic OTU domain, and a ubiquitin-interacting motif (UIM). OTUD1 preferentially hydrolyzes lysine-63-linked ubiquitin chains in vitro; however, recent studies indicate that OTUD1 cleaves various ubiquitin linkages, and is involved in the regulation of multiple cellular functions. Thus, OTUD1 predominantly functions as a tumor suppressor by targeting p53, SMAD7, PTEN, AKT, IREB2, YAP, MCL1, and AIF. Furthermore, OTUD1 regulates antiviral signaling, innate and acquired immune responses, and cell death pathways. Similar to Nrf2, OTUD1 contains a KEAP1-binding ETGE motif in its APGR and regulates the reactive oxygen species (ROS)-mediated oxidative stress response and cell death. Importantly, in addition to its association with various cancers, including multiple myeloma, OTUD1 is involved in acute graft-versus-host disease and autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and ulcerative colitis. Thus, OTUD1 is an important DUB as a therapeutic target for a variety of diseases.

Keywords: KEAP1; OTUD1; antiviral response; cancer; cell death; deubiquitinating enzyme; ubiquitin.

Figure 2

Effects of OTUD1 on tumorigenesis. (A) OTUD1 stabilizes p53 [21]. (B) Deubiquitination of SMAD7 by OTUD1 inhibits the TGF-β/SMAD signaling pathway and suppresses metastasis [22]. (C) OTUD1 stabilizes PTEN, resulting in the suppression of the AKT and NF-κB signaling pathways [23]. (D) OTUD1 binds AKT through the N-terminal aa 92–127 and inhibits its activity [24]. (E) OTUD1 regulates iron metabolism through the deubiquitination of IREB2 and suppresses colorectal cancer [26].

Figure 3

OTUD1 regulates YAP signaling and MCL1 degradation in tumorigenesis. (A) OTUD1 regulates the YAP signal [31]. (B) OTUD1 inhibits MCL1 degradation [35]. (C) OTUD1 regulates MCL1 degradation, mitochondrial AIF function, and cell death [36].

Figure 4

OTUD1 regulates antiviral and innate immune responses, and mutations in OTUD1 are associated with autoimmune diseases. (A) OTUD1 regulates the IRF3-mediated type I IFN production pathway as an antiviral response [37,38,39]. (B) Mutations in OTUD1 are associated with autoimmune diseases [41]. The amino acid mutations in OTUD1 and associated autoimmune diseases are shown. UC, ulcerative colitis; SLE, systemic lupus erythematosus; RA, rheumatoid arthritis. (C) OTUD1 regulates CARD9-mediated NF-κB and MAPK signaling pathways upon fungal infection [43,44]. (D) OTUD1 cleaves the K63-linked ubiquitin chain on RIPK1 and regulates the NF-κB pathway [45].

Figure 5

OTUD1 regulates cell death pathways. (A) OTUD1 stabilizes Bim and induces apoptosis [49]. (B) OTUD1 suppresses the canonical NF-κB and TNF-α-induced apoptosis and necroptosis pathways by cleaving the K63-linked ubiquitin chain [19]. (C) OTUD1 binds KEAP1 through the ETGE motif in the APGR of OTUD1. (D) The amino acid sequence alignment of ETGE motifs in OTUD1 and Nrf2. h: human, m: mouse, c: chicken, z: zebrafish. (E) OTUD1 deficiency affects the intracellular molecular mass of the KEAP1-containing complex. Cited from Ref. [19].

Figure 6

Extended cellular functions of OTUD1. (A) OTUD1 affects multiple myeloma through the regulation of ER-associated degradation of PRDX4 [51]. (B) OTUD1 is involved in aGVHD through the regulation of Notch2-ICD degradation, and dapagliflozin may be an inhibitor of OTUD1 [52]. (C) OTUD1 resolves stalled translation [56]. (D) OTUD1 promotes angiotensin-II-induced vascular remodeling by deubiquitinating SMAD3 [57].

Figure 1

Domain structures of OTU family deubiquitinating enzymes (DUBs). The seventeen human OTU family DUBs are classified into four subfamilies, and the total numbers of amino acid residues and domain organizations are shown. OTU, ovarian tumor protease; APGR, Ala-, Pro-, and Gly-rich region; UIM, ubiquitin-interacting motif; UBX, ubiquitin regulatory X; Tudor, Tudor domain; ZF, zinc finger; NLS, nuclear localization signal; UBA, ubiquitin-associated; AnkUBD, ankyrin repeat ubiquitin-binding domain; UBL, ubiquitin-like; PIM, PUB domain-interacting motif.