Activation and regulation of pathogen sensor RIG-I

Patel, Jenish; Garcı́a-Sastre, Adolfo

doi:10.1016/j.cytogfr.2014.08.005

Cited by 43 publications

(39 citation statements)

References 136 publications

(141 reference statements)

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“…The phosphorylation and activation of TBK1 is essential for IRF3 activation and type I IFN production downstream of RIG-I and MDA-5 (11,12). Regulation of TBK1 activity is a key step in antiviral innate immunity, because excessive activation of type I IFN signaling results in immune disorder (13,14).…”

Section: Discussionmentioning

confidence: 99%

“…Although sufficient production of type I IFN is crucial for virus clearance, uncontrolled and excessive type I IFN expression causes pathological immune response to the host or autoimmune disorders, and thus host cells have developed distinct strategies to tightly regulate the activation of antiviral signaling and maintain the homeostasis of both the innate and adaptive immunity (10)(11)(12). As a critical kinase and central player involved in type I IFN signaling, TBK1 activation can be regulated by multiple molecules in various ways, such as phosphorylation, ubiquitination, and kinase activity modulation (13,14).…”

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confidence: 99%

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Phosphatase PP4 Negatively Regulates Type I IFN Production and Antiviral Innate Immunity by Dephosphorylating and Deactivating TBK1

Zhan

Cao

Xie

et al. 2015

The Journal of Immunology

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The effective recognition of viral infection and subsequent type I IFN production is essential for the host antiviral innate immune responses. The phosphorylation and activation of kinase TANK-binding kinase 1 (TBK1) plays crucial roles in the production of type I IFN mediated by TLR and retinoic acid–inducible gene I–like receptors. Type I IFN expression must be tightly regulated to prevent the development of immunopathological disorders. However, how the activated TBK1 is negatively regulated by phosphatases remains poorly understood. In this study, we identified a previously unknown role of protein phosphatase (PP)4 by acting as a TBK1 phosphatase. PP4 expression was upregulated in macrophages infected with RNA virus, vesicular stomatitis virus, and Sendai virus in vitro and in vivo. Knockdown of PP4C, the catalytic subunit of PP4, significantly increased type I IFN production in macrophages and dentritic cells triggered by TLR3/4 ligands, vesicular stomatitis virus, and Sendai virus, and thus inhibited virus replication. Similar results were also found in peritoneal macrophages with PP4C silencing in vivo and i.p. infection of RNA virus. Accordingly, ectopic expression of PP4C inhibited virus-induced type I IFN production and promoted virus replication. However, overexpression of a phosphatase-dead PP4C mutant abolished the inhibitory effects of wild-type PP4C on type I IFN production. Mechanistically, PP4 directly bound TBK1 upon virus infection, then dephosphorylated TBK1 at Ser172 and inhibited TBK1 activation, and subsequently restrained IFN regulatory factor 3 activation, resulting in suppressed production of type I IFN and IFN-stimulated genes. Thus, serine/threonine phosphatase PP4 functions as a novel feedback negative regulator of RNA virus-triggered innate immunity.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Phosphatase PP4 Negatively Regulates Type I IFN Production and Antiviral Innate Immunity by Dephosphorylating and Deactivating TBK1

Zhan

Cao

Xie

et al. 2015

The Journal of Immunology

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“…The second category consists of different families of intracellular PRRs that are expressed in the cytoplasm and/or the nucleus of most mammalian cell types. These include, among others, the RLRs retinoic acid-inducible gene I (RIG-I), melanoma differentiation associated gene 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2), that specifically sense cytoplasmic non-self viral RNA [24–26]; and a group of cytosolic DNA sensors such as cGAS, that recognize pathogen-derived as well as cellular DNA in the cytoplasm [26, 27]. …”

Section: Innate Immune Sensing Of Flavivirusesmentioning

confidence: 99%

Antagonism of type I interferon by flaviviruses

Miorin

Maestre

Fernández-Sesma

et al. 2017

Biochemical and Biophysical Research Communications

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The prompt and tightly controlled induction of type I interferon is a central event of the immune defense against viral infection. Flaviviruses comprise a large family of arthropod-borne positive-stranded RNA viruses, many of which represent a serious threat to global human health due to their high rates of morbidity and mortality. All flaviviruses studied so far have been shown to counteract the host’s immune response to establish a productive infection and facilitate viral spread. Here, we review the current knowledge on the main strategies that human pathogenic flaviviruses utilize to escape both type I IFN induction and effector pathways. A better understanding of the specific mechanisms by which flaviviruses activate and evade innate immune responses is critical for the development of better therapeutics and vaccines.

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“…During virus infection, viral DNA and RNA are detected by a myriad of PRRs whose activation elicits antiviral responses and inflammation [1,2]. To mediate the innate immune response, binding of RNA or DNA to PRRs results in activation of NF-κB, IRFs, AP-1 and other transcription factors followed by pro-inflammatory gene expression.…”

Section: Introductionmentioning

confidence: 99%

Inflammasome control of viral infection

Lupfer

Malik

Kanneganti

2015

Current Opinion in Virology

134

122

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The inflammasome is a caspase-1 containing complex that activates the proinflammatory cytokines IL-1β and IL-18 and results in the proinflammatory cell death known as pyroptosis. Numerous recent publications have highlighted the importance of inflammasome activation in the control of virus infection. Inflammasome activation during viral infection is dependent on a variety of upstream receptors including the NOD-Like receptor, RIG-I-Like receptor and AIM2-Like receptor families. Various receptors also function in inflammasome activation in different cellular compartments, including the cytoplasm and the nucleus. The effectiveness of inflammasomes at suppressing virus replication is highlighted by the prevalence and diversity of virus encoded inflammasome inhibitors. Also, the host has a myriad of regulatory mechanisms in place to prevent unwanted inflammasome activation and overt inflammation. Finally, recent reports begin to suggest that inflammasome activation and inflammasome modulation may have important clinical applications. Herein, we highlight recent advances and discuss potential future directions toward understanding the role of inflammasomes during virus infection.

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Activation and regulation of pathogen sensor RIG-I

Cited by 43 publications

References 136 publications

Phosphatase PP4 Negatively Regulates Type I IFN Production and Antiviral Innate Immunity by Dephosphorylating and Deactivating TBK1

Phosphatase PP4 Negatively Regulates Type I IFN Production and Antiviral Innate Immunity by Dephosphorylating and Deactivating TBK1

Antagonism of type I interferon by flaviviruses

Inflammasome control of viral infection

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