Ubiquitin-specific Protease 4 Mitigates Toll-like/Interleukin-1 Receptor Signaling and Regulates Innate Immune Activation

Zhou, Fangfang; Zhang, Xiaofei; Dam, Hans van; Dijke, Peter ten; Huang, Huizhe; Zhang, Long

doi:10.1074/jbc.m111.328187

Cited by 77 publications

(64 citation statements)

References 40 publications

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“…In MEF and Raw264.7 cells, polyubiquitination of TRAF6 was increased after IL-1β or LPS treatment, as reported previously [15]. Importantly, depletion of UBE2O by two independent shRNAs enhanced IL-1β-or LPS-induced polyubiquitination of TRAF6 in these cells ( Figure 4A and 4B).…”

Section: Knockdown Of Ube2o Enhances Traf6 Polyubiquitinationsupporting

confidence: 86%

“…Activated TRAF6 functions as an adaptor protein to activate downstream transcription factors. It has been shown that K63 auto-polyubiquitination of TRAF6 is essential for its activation, and is counteracted by the deubiquitnases A20, CYLD, MCPIP1, USP4 or USP2a [14][15][16][17][18]25]. In our study, we found that UBE2O binds endogenous TRAF6 and inhibits both K48-and K63-polyubiquitination of TRAF6.…”

Section: Discussionsupporting

confidence: 56%

“…Inappropriate activation of NF-κB leads to unrestrained innate immune responses and a wide range of human diseases, such as septic shock and rheumatoid arthritis [1,2]. Multiple negative regulators are thus employed to avoid uncontrolled NF-κB activation [14][15][16][17][18]25]. In this article, we demonstrate that UBE2O is involved in regulating TRAF6-mediated NF-κB activation.…”

Section: Discussionmentioning

confidence: 77%

“…The constructs were confirmed by DNA sequencing. The expression constructs HA-Ub-WT, HA-Ub-K48R (only lysine 48 mutated to arginine), HA-Ub-K63R (only lysine 63 mutated to arginine), HA-Ub-K48 (all lysines except lysine 48 mutated to arginines), HA-Ub-K63 (all lysines except lysine 63 mutated to arginines), and the NF-κB and AP-1 reporters have been described previously [15,26]. Flag-TLR4 (Addgene plasmid 27148) was a gift of Bruce Beutler (UT Southwestern Medical Center, USA) [27].…”

Section: Cell Culture and Plasmidsmentioning

confidence: 99%

“…npg have been described to regulate NF-κB signaling by removing ubiquitin chains from TRAF6 [14][15][16][17][18]. Hence, modulation of TRAF6 polyubiquitination is an important way to control NF-κB signaling.…”

Section: Introductionmentioning

confidence: 99%

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UBE2O negatively regulates TRAF6-mediated NF-κB activation by inhibiting TRAF6 polyubiquitination

Zhang

et al. 2013

Cell Res

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Tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) is a key regulator of the activation of transcription factor NF-κB by the interleukin-1 receptor (IL-1R)/Toll-like receptor (TLR) superfamily. Recruitment of TRAF6 to the receptor-associated IRAK1-IRAK4-MyD88 adaptor protein complex induces lysine 63 (K63) autopolyubiquitination of TRAF6, which leads to further recruitment of downstream regulators, such as TAB2/3 and TAK1, and subsequently triggers NF-κB activation. Here, we identified the putative E2 ubiquitin-conjugating (UBC) enzyme UBE2O as a novel negative regulator of TRAF6-dependent NF-κB signaling. We found that UBE2O binds to TRAF6 to inhibit its K63-polyubiquitination, and to prevent the activation of NF-κB by IL-1β and lipopolysaccharides (LPS). We further show that the inhibitory effect of UBE2O is independent of its carboxy-terminal UBC domain. In contrast, we found that UBE2O acts to disrupt the IL-1β-induced association of TRAF6 with MyD88. These results provide novel insight into the regulation of signaling by IL-1R/TLR and TRAF6.

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Section: Knockdown Of Ube2o Enhances Traf6 Polyubiquitinationsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 77%

Section: Cell Culture and Plasmidsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

UBE2O negatively regulates TRAF6-mediated NF-κB activation by inhibiting TRAF6 polyubiquitination

Zhang

et al. 2013

Cell Res

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The Functional Deubiquitinating Enzymes in Control of Innate Antiviral Immunity

Zong

Zhang

et al. 2020

Advanced Science

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Innate antiviral immunity is the first line of host defense against invading viral pathogens. Immunity activation primarily relies on the recognition of pathogen‐associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs). Viral proteins or nucleic acids mainly engage three classes of PRRs: Toll‐like receptors (TLRs), retinoic acid‐inducible gene I (RIG‐I)‐like receptors (RLRs), and DNA sensor cyclic GMP‐AMP (cGAMP) synthase (cGAS). These receptors initiate a series of signaling cascades that lead to the production of proinflammatory cytokines and type I interferon (IFN‐I) in response to viral infection. This system requires precise regulation to avoid aberrant activation. Emerging evidence has unveiled the crucial roles that the ubiquitin system, especially deubiquitinating enzymes (DUBs), play in controlling immune responses. In this review, an overview of the most current findings on the function of DUBs in the innate antiviral immune pathways is provided. Insights into the role of viral DUBs in counteracting host immune responses are also provided. Furthermore, the prospects and challenges of utilizing DUBs as therapeutic targets for infectious diseases are discussed.

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Deubiquitylating Enzymes in Cancer and Immunity

Ren,

Yu,

Liu

et al. 2023

Advanced Science

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Deubiquitylating enzymes (DUBs) maintain relative homeostasis of the cellular ubiquitome by removing the post‐translational modification ubiquitin moiety from substrates. Numerous DUBs have been demonstrated specificity for cleaving a certain type of ubiquitin linkage or positions within ubiquitin chains. Moreover, several DUBs perform functions through specific protein–protein interactions in a catalytically independent manner, which further expands the versatility and complexity of DUBs’ functions. Dysregulation of DUBs disrupts the dynamic equilibrium of ubiquitome and causes various diseases, especially cancer and immune disorders. This review summarizes the Janus‐faced roles of DUBs in cancer including proteasomal degradation, DNA repair, apoptosis, and tumor metastasis, as well as in immunity involving innate immune receptor signaling and inflammatory and autoimmune disorders. The prospects and challenges for the clinical development of DUB inhibitors are further discussed. The review provides a comprehensive understanding of the multi‐faced roles of DUBs in cancer and immunity.

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Ubiquitin-specific Protease 4 Mitigates Toll-like/Interleukin-1 Receptor Signaling and Regulates Innate Immune Activation

Cited by 77 publications

References 40 publications

UBE2O negatively regulates TRAF6-mediated NF-κB activation by inhibiting TRAF6 polyubiquitination

UBE2O negatively regulates TRAF6-mediated NF-κB activation by inhibiting TRAF6 polyubiquitination

The Functional Deubiquitinating Enzymes in Control of Innate Antiviral Immunity

Deubiquitylating Enzymes in Cancer and Immunity

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