TRIM4 modulates type I interferon induction and cellular antiviral response by targeting RIG-I for K63-linked ubiquitination

Yan, Jie; Li, Qi; Mao, Aiping; Hu, Mingming; Shu, Hong‐Bing

doi:10.1093/jmcb/mju005

Cited by 173 publications

(173 citation statements)

References 29 publications

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“…Overexpression of TRIM4 led to increased IFN induction following infection with Sendai virus (SeV), a paramyxovirus known to be detected by RIG-I [74]. More detailed analysis indicated that TRIM4 interacted with RIG-I and led to the K63-linked ubiquitination of K154, K164, and K172 in the CARDs.…”

Section: The Role Of Ubiquitin In Rlr Signal Transductionmentioning

confidence: 99%

Ubiquitination in the antiviral immune response

2015

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Ubiquitination has long been known to regulate fundamental cellular processes through the induction of proteasomal degradation of target proteins. More recently, ‘atypical’ nondegradative types of polyubiquitin chains have been appreciated as important regulatory moieties by modulating the activity or subcellular localization of key signaling proteins. Intriguingly, many of these non-degradative types of ubiquitination regulate the innate sensing pathways initiated by pattern recognition receptors (PRRs), ultimately coordinating an effective antiviral immune response. Here we discuss recent advances in understanding the functional roles of degradative and atypical types of ubiquitination in innate immunity to viral infections, with a specific focus on the signaling pathways triggered by RIG-I-like receptors, Toll-like receptors, and the intracellular viral DNA sensor cGAS.

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Section: The Role Of Ubiquitin In Rlr Signal Transductionmentioning

confidence: 99%

Ubiquitination in the antiviral immune response

2015

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“…Quantitative real-time PCR (qPCR) assays were performed as previously described (26)(27)(28)(29). Total RNA from mouse or human cells was isolated using TRIzol reagent (Invitrogen).…”

Section: Quantitative Real-time Pcrmentioning

confidence: 99%

TRIM38 Negatively Regulates TLR3/4-Mediated Innate Immune and Inflammatory Responses by Two Sequential and Distinct Mechanisms

Xie

Yang

et al. 2015

The Journal of Immunology

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Tripartite motif (TRIM)38 is an E3 ubiquitin ligase that was reported to regulate signaling in innate immune and inflammatory responses in certain cell lines. In this study, we show that Trim38 deficiency markedly increased TLR3- and TLR4-mediated induction of type I IFNs and proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6, in immune cells and in vivo. Trim38 deficiency also caused the mice to be more susceptible to death triggered by polyinosinic-polycytidylic acid, LPS, and Salmonella typhimurium. Mechanistically, TRIM38 catalyzed K48-linked polyubiquitination of the TLR3/4 adapter protein TIR domain–containing adapter-inducing IFN-β at K228 and promoted its proteasomal degradation in immune cells. Moreover, Trim38 was highly induced by type I IFNs, which then negatively regulated TNF-α/IL-1β signaling in IFN-β–primed immune cells, but not unprimed immune cells, by mediating degradation of Tab2 in a lysosomal-dependent process. These results suggest that Trim38 negatively regulates TLR3/4-mediated innate immune and inflammatory responses by two sequential and distinct mechanisms. This study increases our understanding of how the innate immune response is initiated during the early phase of infection to defend against microbial invasion and is efficiently terminated during the late phase to prevent excessive and harmful inflammatory responses.

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“…Accumulating evidence suggests that many TRIM proteins are involved in antiviral immunity. For example, TRIM4 and TRIM25 regulate the ubiquitination of RIG-I to promote type I IFN production and NF-κB activity [20,21]. Furthermore, TRIM32 and TRIM56 positively regulate DNA virus-induced type I IFN signaling by interacting with STING and targeting it for K63-linked ubiquitination [22,23].…”

Section: Introductionmentioning

confidence: 99%

TRIM9 short isoform preferentially promotes DNA and RNA virus-induced production of type I interferon by recruiting GSK3β to TBK1

et al. 2016

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Type I interferon (IFN) is an important component of antiviral innate immune signaling mediated by viral DNAand RNA recognition by the DNA sensor cGAS and RNA sensors RIG-I and MDA5. Activation of these DNA and RNA sensors leads to the recruitment of STING and MAVS, respectively, and converges on TANK-binding kinase 1 (TBK1) signaling for subsequent phosphorylation of IFN regulatory factor 3 (IRF3). However, the mechanisms that control TBK1 activation are still poorly defined. Here, we identify tripartite motif 9 short isoform (TRIM9s) as a positive regulator in type I IFN signaling. Upon viral infection, TRIM9s undergoes Lys-63-linked auto-polyubiquitination and serves as a platform to bridge GSK3β to TBK1, leading to the activation of IRF3 signaling. Interestingly, we found that TRIM9s selectively inhibits the production of pro-inflammatory cytokines, but enhances the expression of type I IFNs as well as IFN-stimulated genes, in response to viral infection. Our findings reveal novel dual functions of TRIM9s in antiviral immunity, which serve to balance pro-inflammatory response and production of type I IFNs.

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TRIM4 modulates type I interferon induction and cellular antiviral response by targeting RIG-I for K63-linked ubiquitination

Cited by 173 publications

References 29 publications

Ubiquitination in the antiviral immune response

Ubiquitination in the antiviral immune response

TRIM38 Negatively Regulates TLR3/4-Mediated Innate Immune and Inflammatory Responses by Two Sequential and Distinct Mechanisms

TRIM9 short isoform preferentially promotes DNA and RNA virus-induced production of type I interferon by recruiting GSK3β to TBK1

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