OTUD4 Is a Phospho-Activated K63 Deubiquitinase that Regulates MyD88-Dependent Signaling

Zhao, Yu; Mudge, Miranda C.; Soll, Jennifer M.; Rodrigues, Rachel B.; Byrum, Andrea K.; Schwarzkopf, Elizabeth A.; Bradstreet, Tara R.; Gygi, Steven P.; Edelson, Brian T.; Mosammaparast, Nima

doi:10.1016/j.molcel.2018.01.009

Cited by 74 publications

(85 citation statements)

References 37 publications

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“…Here, ATX3 assists the p97‐dependent substrate extraction of the substrates from the ER or chromatin by trimming their associated ubiquitin chains to allow timely processing of the substrates (extraction from ER or chromatin), most probably through the central pore of p97 in a manner recently described (Bodnar & Rapoport, ). The different roles of ATX3 on RNF8 could be potentially regulated by two different ubiquitin chain types on RNF8 (K48 and K63; Fig EV1D) and/or the phosphorylation status of ATX3 (Matos et al , ), as recently described for the DUB OTUD4 (Zhao et al , ). Unphosphorylated OTUD4 trims K48‐Ub signals from alkylation DNA repair proteins and thus counteracts their proteasomal degradation.…”

Section: Discussionmentioning

confidence: 63%

The p97–Ataxin 3 complex regulates homeostasis of the DNA damage response E3 ubiquitin ligase RNF 8

et al. 2019

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The E3 ubiquitin ligase RNF8 (RING finger protein 8) is a pivotal enzyme for DNA repair. However, RNF8 hyper‐accumulation is tumour‐promoting and positively correlates with genome instability, cancer cell invasion, metastasis and poor patient prognosis. Very little is known about the mechanisms regulating RNF8 homeostasis to preserve genome stability. Here, we identify the cellular machinery, composed of the p97/VCP ubiquitin‐dependent unfoldase/segregase and the Ataxin 3 (ATX3) deubiquitinase, which together form a physical and functional complex with RNF8 to regulate its proteasome‐dependent homeostasis under physiological conditions. Under genotoxic stress, when RNF8 is rapidly recruited to sites of DNA lesions, the p97–ATX3 machinery stimulates the extraction of RNF8 from chromatin to balance DNA repair pathway choice and promote cell survival after ionising radiation (IR). Inactivation of the p97–ATX3 complex affects the non‐homologous end joining DNA repair pathway and hypersensitises human cancer cells to IR. We propose that the p97–ATX3 complex is the essential machinery for regulation of RNF8 homeostasis under both physiological and genotoxic conditions and that targeting ATX3 may be a promising strategy to radio‐sensitise BRCA‐deficient cancers.

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Section: Discussionmentioning

confidence: 63%

The p97–Ataxin 3 complex regulates homeostasis of the DNA damage response E3 ubiquitin ligase RNF 8

et al. 2019

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“…41,42 However, phosphorylation at the catalytic domain of OTUD4 at Ser202/ 204 activates its K63-specific DUB activity, which targets MyD88 for deubiquitination and thereby downregulates TLR-mediated NF-κB activation. 43 In addition, OTUD4 promotes the repair of DNA alkylation damage in a manner independent of its DUB activity. 41 The K48-specific DUB activity of OTUD4 and the target(s) and the related physiological or pathological significance of such an activity remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Induction of OTUD4 by viral infection promotes antiviral responses through deubiquitinating and stabilizing MAVS

Liuyu

et al. 2018

Cell Res

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The activity and stability of the adapter protein MAVS (also known as VISA, Cardif and IPS-1), which critically mediates cellular antiviral responses, are extensively regulated by ubiquitination. However, the process whereby MAVS is deubiquitinated is unclear.Here, we report that the ovarian tumor family deubiquitinase 4 (OTUD4) targets MAVS for deubiquitination. Viral infection leads to the IRF3/7-dependent upregulation of OTUD4 which interacts with MAVS to remove K48-linked polyubiquitin chains, thereby maintaining MAVS stability and promoting innate antiviral signaling. Knockout or knockdown of OTUD4 impairs RNA virus-triggered activation of IRF3 and NF-κB, expression of their downstream target genes, and potentiates VSV replication in vitro and in vivo. Consistently, Cre-ER Otud4 fl/fl or Lyz2-Cre Otud4 fl/fl mice produce decreased levels of type I interferons and proinflammatory cytokines and exhibit increased sensitivity to VSV infection compared to their control littermates. In addition, reconstitution of MAVS into OTUD4-deficient cells restores virus-induced expression of downstream genes and cellular antiviral responses. Together, our findings uncover an essential role of OTUD4 in virus-triggered signaling and contribute to the understanding of deubiquitination-mediated regulation of innate antiviral responses.

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“…MyD88 could be ubiquitinated by either K48 or K63-linked ubiquitination[10–13]. To investigate the molecular mechanisms of SPOP-mediated degradation of MyD88, we transfected vectors expressing HA-tagged K48 or K63-linked ubiquitin into chicken DF1 cells, and found that overexpression of chSPOP enhanced the K48-linked rather than the K63-linked ubiquitination of chMyD88 (Fig 3A, lanes 3,4).…”

Section: Resultsmentioning

confidence: 99%

“…Excessive inflammation and the production of proinflammatory cytokines and interferons resulting from the misregulation of MyD88 signaling are detrimental to health and might lead to pathological damage, such as cancer and autoimmune diseases [27–29]. Several mechanisms that regulate the activity of MyD88 have been revealed [9–13, 18]. For example, transforming growth factor-β induces the Smad6-dependent recruitment of E3 ubiquitin ligases Smurf1 and Smurf2 to MyD88, targeting them for proteasomal degradation and thereby displaying its anti-inflammatory function [11].…”

Section: Discussionmentioning

confidence: 99%

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SPOP Promotes Ubiquitination and Degradation of MyD88 to Suppress the Innate Immune Response

Wang

et al. 2019

Preprint

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AbstractAs a canonical adaptor for Toll-like receptor (TLR) family, MyD88 has crucial roles in host defence against infection of microbial pathogens and its dysregulation might induce autoimmune diseases. Here we demonstrate that the Cullin 3-based ubiquitin ligase adaptor SPOP recognizes the intermediate domain and degrades chMyD88 through the proteasome pathway. Knockdown or genetic ablation of chSPOP leads to aberrant elevation of the chMyD88 protein. Consequently, ChSPOP negatively regulates the activity of NF-κB pathway and thus the production of IL-1β and IL-8 upon LPS challenge. Furthermore, SPOP deficiency mice are more susceptible to infection of Salmonella typhimurium. Collectively, these findings demonstrate chMyD88 as a bona fide substrate of chSPOP and uncover a mechanism by which chSPOP suppresses the innate immune signaling.Author SummaryMyD88 is a central adaptor mediating the initiate of innate immune response and production of proinflammatory cytokines that restrain pathogens and activate adaptive immunity. Although MyD88 is crucial for the host to prevent pathogenic infection, misregulation of MyD88 abundance might lead to autoimmune diseases. Thus, degradation of MyD88 is a canonical mechanism to terminate cytokines production. Here we characterized a novel E3 ligase SPOP that target MyD88 for degradation. SPOP attenuated IL1β and IL8 production through K48-linked polyubiquitination and degradation of MyD88 and thus impaired immune responses. SPOP deficient mice show more susceptibility to infection by Salmonella typhimurium. These findings demonstrate that SPOP is a negative regulator of MyD88-dependent pathway activation triggered by LPS and Salmonella typhimurium, which helps the host to maintain immune homeostasis.

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OTUD4 Is a Phospho-Activated K63 Deubiquitinase that Regulates MyD88-Dependent Signaling

Cited by 74 publications

References 37 publications

The p97–Ataxin 3 complex regulates homeostasis of the DNA damage response E3 ubiquitin ligase RNF 8

The p97–Ataxin 3 complex regulates homeostasis of the DNA damage response E3 ubiquitin ligase RNF 8

Induction of OTUD4 by viral infection promotes antiviral responses through deubiquitinating and stabilizing MAVS

SPOP Promotes Ubiquitination and Degradation of MyD88 to Suppress the Innate Immune Response

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