Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation

Liu, Siqi; Cai, Xin; Wu, Jiaxi; Cong, Qian; Chen, Xiang; Li, Tuo; Du, Fenghe; Ren, Junyao; Wu, Ya Fei; Grishin, Nick V.; Chen, Zhijian J.

doi:10.1126/science.aaa2630

Cited by 1,310 publications

(1,207 citation statements)

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“…The transcription factor IRF3 is important for the induction of type III IFNs (Lazear et al, 2015), and activation of IRF3 is dependent on phosphorylation at multiple sites (hyperphosphorylation) (Lin et al, 1999;Liu et al, 2015;Servant et al, 2001). Here, we studied the phosphorylation pattern of IRF3 following CVB3 infection and, to our knowledge, provide the first evidence that hyperphosphorylation of IRF3 does not occur after CVB3 infection (Fig.…”

Section: Discussionmentioning

confidence: 94%

“…IRF3 is constitutively expressed and resides primarily in the cytosol of unstimulated cells. Upon stimulation, IRF3 is phosphorylated at multiple sites in the C-terminal domain (hyperphosphorylation) and this is required for dimerization, transmigration to the nucleus and binding to elements in the promoter regions of genes such as the type I IFN genes (Jensen & Thomsen, 2012;Liu et al, 2015).…”

Section: Cvb3 Infection Fails To Induce Hyperphosphorylation Of Irf3mentioning

confidence: 99%

“…Upon ligand engagement, TLR3 recruits TIR domain-containing adaptor inducing IFNb (TRIF, also known as TICAM) whereas MDA5 and RIG-I interact with mitochondrial antiviral signalling protein (IPS1, also know as MAVS, VISA and CARDIF). The signalling pathways converge in the activation of tank-binding kinase 1 (TBK1) and the inducible Ikb kinase (IKK) complex, which leads to activation of the transcription factors Interferon regulatory factor 3(IRF3) and NF-kB and the induced expression of type I and III IFNs (Jensen & Thomsen, 2012;Liu et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Coxsackievirus counters the host innate immune response by blocking type III interferon expression

Lind

Svedin

Domsgen

et al. 2016

Journal of General Virology

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Type I IFNs play an important role in the immune response to enterovirus infections. Their importance is underscored by observations showing that many enteroviruses including coxsackie B viruses (CVBs) have developed strategies to block type I IFN production. Recent studies have highlighted a role for the type III IFNs (also called IFNls) in reducing permissiveness to infections with enteric viruses including coxsackievirus. However, whether or not CVBs have measures to evade the effects of type III IFNs remains unknown. By combining virus infection studies and different modes of administrating the dsRNA mimic poly I : C, we discovered that CVBs target both Toll-like receptor 3-and MDA5/RIG-I-mediated type III IFN expression. Consistent with this, the cellular protein expression levels of the signal transduction proteins TRIF and IPS1 were reduced and no hyperphosphorylation of interferon regulatory factor 3 was observed following infection with the virus. Notably, decreased expression of full-length TRIF and IPS1 and the appearance of cleavage products was observed upon both CVB3 infection and in cellular protein extracts incubated with recombinant 2A pro , indicating an important role for the viral protease in subverting the cellular immune system. Collectively, our study reveals that CVBs block the expression of type III IFNs, and that this is achieved by a similar mechanism as the virus uses to block type I IFN production. We also demonstrate that the virus blocks several intracellular viral recognition pathways of importance for both type I and III IFN production. The simultaneous targeting of numerous arms of the host immune response may be required for successful viral replication and dissemination.

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Section: Discussionmentioning

confidence: 94%

Section: Cvb3 Infection Fails To Induce Hyperphosphorylation Of Irf3mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Coxsackievirus counters the host innate immune response by blocking type III interferon expression

Lind

Svedin

Domsgen

et al. 2016

Journal of General Virology

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“…ii) STING (stimulator of interferon genes) is an important component of the signaling cascade that leads to the activation of IFN (23,24). Recent studies show that STING is actively maintained and exported via exosomes from infected cells to uninfected cells (17).…”

Section: Discussionmentioning

confidence: 99%

miR-H28 and miR-H29 expressed late in productive infection are exported and restrict HSV-1 replication and spread in recipient cells

Han

Liu

Chen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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We report on the properties and function of two herpes simplex virus-1 (HSV-1) microRNAs (miRNAs) designated “miR-H28” and “miR-H29.” Both miRNAs accumulate late in productive infection at a time when, for the most part, viral DNA and proteins have been made. Ectopic expression of miRNA mimics in human cells before infection reduced the accumulation of viral mRNAs and proteins, reduced plaque sizes, and at vey low multiplicities of infection reduced viral yields. The specificity of the miRNA mimics was tested in two ways. First, ectopic expression of mimics carrying mutations in the seed sequence was ineffective. Second, in similar tests two viral miRNAs made early in productive infection also had no effect. Both miR-H28 and miR-H29 are exported from infected cells in exosomes. A noteworthy finding is that both miR-H28 and miR-H29 were absent from murine ganglia harboring latent virus but accumulated in ganglia in which the virus was induced to reactivate. The significance of these findings rests on the principle that the transmission of HSV from person to person is by physical contact between the infected tissues of the donor and those of uninfected recipient. Diminished size of primary or recurrent lesions could be predicted to enhance person-to-person transmission. Reduction in the amount of reactivating latent virus would reduce the risk of retrograde transport to the CNS but would not interfere with anterograde transport to a site at or near the site of initial infection.

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“…cGAMP, the defined endogenous ligand of STING [59], then induces conformational changes in STING, which causes its subsequent trafficking from the endoplasmic reticulum to perinuclear vesicles [60]. This results in the recruitment and phosphorylation of TANK-binding kinase 1 (TBK1), which in turn phosphorylates and activates IRF3 leading to the activation of type I IFN transcription [61]. Based on this model of STING pathway activation, the presence of tumor-derived DNA has been examined in the cytosol of intratumoral APCs and does appear to be found there [45,53].…”

Section: The Sting Pathway and Innate Immune Sensing Of Tumorsmentioning

confidence: 99%

Innate immune signaling and regulation in cancer immunotherapy

et al. 2016

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A pre-existing T cell-inflamed tumor microenvironment has prognostic utility and also can be predictive for response to contemporary cancer immunotherapies. The generation of a spontaneous T cell response against tumor-associated antigens depends on innate immune activation, which drives type I interferon (IFN) production. Recent work has revealed a major role for the STING pathway of cytosolic DNA sensing in this process. This cascade of events contributes to the activation of Batf3-lineage dendritic cells (DCs), which appear to be central to anti-tumor immunity. Non-T cell-inflamed tumors lack chemokines for Batf3 DC recruitment, have few Batf3 DCs, and lack a type I IFN gene signature, suggesting that failed innate immune activation may be the ultimate cause for lack of spontaneous T cell activation and accumulation. With this information in hand, new strategies for triggering innate immune activation and Batf3 DC recruitment are being developed, including novel STING agonists for de novo immune priming. Ultimately, the successful development of effective innate immune activators should expand the fraction of patients that can respond to immunotherapies, such as with checkpoint blockade antibodies.

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Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation

Cited by 1,310 publications

References 48 publications

Coxsackievirus counters the host innate immune response by blocking type III interferon expression

Coxsackievirus counters the host innate immune response by blocking type III interferon expression

miR-H28 and miR-H29 expressed late in productive infection are exported and restrict HSV-1 replication and spread in recipient cells

Innate immune signaling and regulation in cancer immunotherapy

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