OTUD5 promotes innate antiviral and antitumor immunity through deubiquitinating and stabilizing STING

Guo, Yunyun; Jiang, Fei; Kong, Lingli; Wu, Haifeng; Zhang, Honghai; Chen, Xiaorong; Zhao, Jian; Cai, Baoshan; Li, Yanqi; Hong, Chun Pyo; Yi, Fan; Zhang, Lei; Liu, Bingyu; Zheng, Yi; Zhang, Lingqiang; Gao, Chengjiang

doi:10.1038/s41423-020-00531-5

Cited by 62 publications

(47 citation statements)

References 34 publications

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“… Signaling molecule Classification Regulator Function Ref. 2′,3′-cGAMP Positive LRRC8 Transportation 290 Negative ENPP1 Hydrolysis 291 Physical interaction & hydrolysis 292 STING PTMs Positive AMFR/INSIG1 K27-linked ubiquitination 304 MUL1 K63-linked ubiquitination 301 TRAF6 K63-linked ubiquitination 302 UBXN3B K63-linked ubiquitination 303 RNF115 K63-linked ubiquitination 59 CYLD Deubiquitination 308 OTUD5 Deubiquitination 309 USP44 Deubiquitination 307 USP20/USP18 Deubiquitination 305 USP20 Deubiquitination 306 iRhom2 Deubiquitination 310 CSK Phosphorylation 315 TBK1 Phosphorylation 313 STING Palmitoylation 312 Negative USP13 K33-linked ubiquitination 324 ...…”

Section: Role Of Ptms In Regulating Signal Transductionmentioning

confidence: 99%

“…Therefore, any factor that disrupts the K48-linked polyubiquitin chain may activate signal transduction. The DUBs USP20/USP18 305 , 306 , USP44 307 , CYLD 308 , OTUD5 309 , and iRhom2 310 remove K48-linked polyubiquitin chains from STING and ultimately boost innate antiviral responses. Palmitoylation plays an important role in regulating protein transport, stability, and cellular localization in host cells.…”

Section: Regulation Of Sting By Host Factorsmentioning

confidence: 99%

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Regulation of antiviral innate immune signaling and viral evasion following viral genome sensing

et al. 2021

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A harmonized balance between positive and negative regulation of pattern recognition receptor (PRR)-initiated immune responses is required to achieve the most favorable outcome for the host. This balance is crucial because it must not only ensure activation of the first line of defense against viral infection but also prevent inappropriate immune activation, which results in autoimmune diseases. Recent studies have shown how signal transduction pathways initiated by PRRs are positively and negatively regulated by diverse modulators to maintain host immune homeostasis. However, viruses have developed strategies to subvert the host antiviral response and establish infection. Viruses have evolved numerous genes encoding immunomodulatory proteins that antagonize the host immune system. This review focuses on the current state of knowledge regarding key host factors that regulate innate immune signaling molecules upon viral infection and discusses evidence showing how specific viral proteins counteract antiviral responses via immunomodulatory strategies.

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Section: Role Of Ptms In Regulating Signal Transductionmentioning

confidence: 99%

Section: Regulation Of Sting By Host Factorsmentioning

confidence: 99%

Regulation of antiviral innate immune signaling and viral evasion following viral genome sensing

et al. 2021

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“…These include ATXN3 and OTUD5, respectively, causing the Machado-Joseph disease and a X-linked multiple congenital anomalies-neurodevelopmental syndrome ( Kawaguchi et al, 1994 ; Beck et al, 2021 ; Tripolszki et al, 2021 ). Indeed, by removing proteolytic poly ubiquitin chains from the cytosolic DNA sensor STING, OTUD5 facilitates antiviral innate signaling and the subsequent transcription of type I IFN genes ( Guo et al, 2020a ). Likewise, ATXN3 has been shown to exacerbate type I antiviral response via the deubiquitination and stabilization of histone deacetylase 3 (HDAC3) ( Feng et al, 2018 ).…”

Section: Ndd-associated E3 Ubiquitin Ligases and Their Roles In The Immune Responsementioning

confidence: 99%

Neurodevelopmental Disorders (NDD) Caused by Genomic Alterations of the Ubiquitin-Proteasome System (UPS): the Possible Contribution of Immune Dysregulation to Disease Pathogenesis

Ebstein

Küry

Papendorf

et al. 2021

Front. Mol. Neurosci.

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Over thirty years have passed since the first description of ubiquitin-positive structures in the brain of patients suffering from Alzheimer’s disease. Meanwhile, the intracellular accumulation of ubiquitin-modified insoluble protein aggregates has become an indisputable hallmark of neurodegeneration. However, the role of ubiquitin and a fortiori the ubiquitin-proteasome system (UPS) in the pathogenesis of neurodevelopmental disorders (NDD) is much less described. In this article, we review all reported monogenic forms of NDD caused by lesions in genes coding for any component of the UPS including ubiquitin-activating (E1), -conjugating (E2) enzymes, ubiquitin ligases (E3), ubiquitin hydrolases, and ubiquitin-like modifiers as well as proteasome subunits. Strikingly, our analysis revealed that a vast majority of these proteins have a described function in the negative regulation of the innate immune response. In this work, we hypothesize a possible involvement of autoinflammation in NDD pathogenesis. Herein, we discuss the parallels between immune dysregulation and neurodevelopment with the aim at improving our understanding the biology of NDD and providing knowledge required for the design of novel therapeutic strategies.

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“…Similarly, OTUD5 promotes the protein stability of STING via cleaving the K48-linked polyubiquitin chains. The knockout of OTUD5 leads to faster turnover of STING and impairs IFN-I signaling following cytosolic DNA stimulation, whereas Lyz2-Cre Otud5 fl/Y mice and CD11-Cre Otud5 fl/Y mice show higher susceptibility to HSV-1 infection than their corresponding control littermates ( 69 ). Among the USP members, USP1 functions as a viral infection-induced physiological enhancer of TBK1 expression when bound to USP1 the K48-linked polyubiquitination of TBK1, resulting in enhanced TLR3/4 and RIG-I-induced IRF3 activation and IFNβ secretion ( 74 ).…”

Section: Dubs Regulate Ifn-i-mediated Antiviral Responses Via Their Protease Activitymentioning

confidence: 99%

An Integrated View of Deubiquitinating Enzymes Involved in Type I Interferon Signaling, Host Defense and Antiviral Activities

Qian

Zhu

et al. 2021

Front. Immunol.

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Viral infectious diseases pose a great challenge to human health around the world. Type I interferons (IFN-Is) function as the first line of host defense and thus play critical roles during virus infection by mediating the transcriptional induction of hundreds of genes. Nevertheless, overactive cytokine immune responses also cause autoimmune diseases, and thus, tight regulation of the innate immune response is needed to achieve viral clearance without causing excessive immune responses. Emerging studies have recently uncovered that the ubiquitin system, particularly deubiquitinating enzymes (DUBs), plays a critical role in regulating innate immune responses. In this review, we highlight recent advances on the diverse mechanisms of human DUBs implicated in IFN-I signaling. These DUBs function dynamically to calibrate host defenses against various virus infections by targeting hub proteins in the IFN-I signaling transduction pathway. We also present a future perspective on the roles of DUB-substrate interaction networks in innate antiviral activities, discuss the promises and challenges of DUB-based drug development, and identify the open questions that remain to be clarified. Our review provides a comprehensive description of DUBs, particularly their differential mechanisms that have evolved in the host to regulate IFN-I-signaling-mediated antiviral responses.

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OTUD5 promotes innate antiviral and antitumor immunity through deubiquitinating and stabilizing STING

Cited by 62 publications

References 34 publications

Regulation of antiviral innate immune signaling and viral evasion following viral genome sensing

Regulation of antiviral innate immune signaling and viral evasion following viral genome sensing

Neurodevelopmental Disorders (NDD) Caused by Genomic Alterations of the Ubiquitin-Proteasome System (UPS): the Possible Contribution of Immune Dysregulation to Disease Pathogenesis

An Integrated View of Deubiquitinating Enzymes Involved in Type I Interferon Signaling, Host Defense and Antiviral Activities

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