Feline calicivirus strain 2280 p30 antagonizes type I interferon-mediated antiviral innate immunity through directly degrading IFNAR1 mRNA

MDA5 plays a critical role in antiviral innate immunity by functioning as a cytoplasmic double-stranded RNA sensor that can activate type I interferon signaling pathways, but the mechanism for the activation of MDA5 is poorly understood. Here, we show that TRIM65 specifically interacts with MDA5 and promotes K63-linked ubiquitination of MDA5 at lysine 743, which is critical for MDA5 oligomerization and activation. Trim65 deficiency abolishes MDA5 agonist or encephalomyocarditis virus (EMCV)–induced interferon regulatory factor 3 (IRF3) activation and type I interferon production but has no effect on retinoic acid–inducible I (RIG-I), Toll-like receptor 3 (TLR3), or cyclic GMP-AMP synthase signaling pathways. Importantly, Trim65−/− mice are more susceptible to EMCV infection than controls and cannot produce type I interferon in vivo. Collectively, our results identify TRIM65 as an essential component for the MDA5 signaling pathway and provide physiological evidence showing that ubiquitination is important for MDA5 oligomerization and activation.

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Faculty Opinions recommendation of Mapping a dynamic innate immunity protein interaction network regulating type I interferon production.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13335981.14702151 ◽

2011 ◽

Author(s):

Ralf Bartenschlager ◽

Marco Binder

Keyword(s):

Innate Immunity ◽

Protein Interaction ◽

Protein Interaction Network ◽

Type I Interferon ◽

Interaction Network ◽

Type I ◽

Interferon Production ◽

Immunity Protein

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E3 ligase Nedd4l promotes antiviral innate immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3

Nature Communications ◽

10.1038/s41467-021-21456-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Peng Gao ◽

Xianwei Ma ◽

Ming Yuan ◽

Yulan Yi ◽

Guoke Liu ◽

...

Keyword(s):

Posttranslational Modifications ◽

Type I Interferon ◽

Zinc Fingers ◽

E3 Ligase ◽

Type I ◽

E3 Ligases ◽

Protein Posttranslational Modifications ◽

Antiviral Innate Immunity

AbstractUbiquitination is one of the most prevalent protein posttranslational modifications. Here, we show that E3 ligase Nedd4l positively regulates antiviral immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3. Deficiency of Nedd4l significantly impairs type I interferon and proinflammatory cytokine production induced by virus infection both in vitro and in vivo. Nedd4l deficiency inhibits virus-induced ubiquitination of TRAF3, the binding between TRAF3 and TBK1, and subsequent phosphorylation of TBK1 and IRF3. Nedd4l directly interacts with TRAF3 and catalyzes K29-linked ubiquitination of Cys56 and Cys124, two cysteines that constitute zinc fingers, resulting in enhanced association between TRAF3 and E3 ligases, cIAP1/2 and HECTD3, and also increased K48/K63-linked ubiquitination of TRAF3. Mutation of Cys56 and Cys124 diminishes Nedd4l-catalyzed K29-linked ubiquitination, but enhances association between TRAF3 and the E3 ligases, supporting Nedd4l promotes type I interferon production in response to virus by catalyzing ubiquitination of the cysteines in TRAF3.

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Inducible microRNA-155 Feedback Promotes Type I IFN Signaling in Antiviral Innate Immunity by Targeting Suppressor of Cytokine Signaling 1

The Journal of Immunology ◽

10.4049/jimmunol.1000491 ◽

2010 ◽

Vol 185 (10) ◽

pp. 6226-6233 ◽

Cited By ~ 277

Author(s):

Pin Wang ◽

Jin Hou ◽

Li Lin ◽

Chunmei Wang ◽

Xingguang Liu ◽

...

Keyword(s):

Innate Immunity ◽

Cytokine Signaling ◽

Type I ◽

Type I Ifn ◽

Suppressor Of Cytokine Signaling ◽

Antiviral Innate Immunity

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A Tug of War: DNA-Sensing Antiviral Innate Immunity and Herpes Simplex Virus Type I Infection

Frontiers in Microbiology ◽

10.3389/fmicb.2019.02627 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 7

Author(s):

Yingying Lin ◽

Chunfu Zheng

Keyword(s):

Innate Immunity ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Type I ◽

Dna Sensing ◽

Simplex Virus ◽

Antiviral Innate Immunity

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Swine Acute Diarrhea Syndrome Coronavirus Nucleocapsid Protein Antagonizes Interferon-β Production via Blocking the Interaction Between TRAF3 and TBK1

Frontiers in Immunology ◽

10.3389/fimmu.2021.573078 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhihai Zhou ◽

Yuan Sun ◽

Jingya Xu ◽

Xiaoyu Tang ◽

Ling Zhou ◽

...

Keyword(s):

Innate Immunity ◽

Acute Diarrhea ◽

Nuclear Translocation ◽

Sendai Virus ◽

Type I ◽

Innate Immune Responses ◽

N Protein ◽

Antiviral Innate Immunity ◽

Diarrhea Syndrome

Swine acute diarrhea syndrome coronavirus (SADS-CoV), first discovered in 2017, is a porcine enteric coronavirus that can cause acute diarrhea syndrome (SADS) in piglets. Here, we studied the role of SADS-CoV nucleocapsid (N) protein in innate immunity. Our results showed that SADS-CoV N protein could inhibit type I interferon (IFN) production mediated by Sendai virus (Sev) and could block the phosphorylation and nuclear translocation of interferon regulatory factor 3 (IRF3). Simultaneously, the IFN-β promoter activity mediated by TANK binding kinase 1 (TBK1) or its upstream molecules in the RLRs signal pathway was inhibited by SADS-CoV N protein. Further investigations revealed that SADS-CoV N protein could counteract interaction between TNF receptor-associated factor 3 (TRAF3) and TBK1, which led to reduced TBK1 activation and IFN-β production. Our study is the first report of the interaction between SADS-CoV N protein and the host antiviral innate immune responses, and the mechanism utilized by SADS-CoV N protein provides a new insight of coronaviruses evading host antiviral innate immunity.

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