Inhibition of RIG-I and MDA5-dependent antiviral response by gC1qR at mitochondria

Xu, Lijuan; Xiao, Nengming; Liu, Feng; Ren, Hongwei; Gu, Jun

doi:10.1073/pnas.0811029106

Cited by 128 publications

(92 citation statements)

References 32 publications

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“…human immunodeficiency virus type 1 Rev (44) and Tat (43), hepatitis C virus core protein (46), EBNA-1 of Epstein-Barr virus (54), and open reading frame P of HSV (55). The intracellular localization and function of p32 have been demonstrated primarily as a mitochondrial membrane protein in harakiri-mediated apoptosis (42), a mitochondrial antiviral signaling protein-interacting protein in RNAinduced retinoic acid-inducible gene I signaling (35), an interactor of splicing factor SF2/alternative splicing factor for RNA splicing (41), and an RNA-interacting protein for the translation of mitochondrial RNA (56). To date, the only viral kinase reported to associate with intracellular p32 is human CMV pUL97, a kinase that phosphorylates nuclear lamina at the inner nuclear membrane (45).…”

Section: Discussionmentioning

confidence: 99%

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p32 Is a Novel Target for Viral Protein ICP34.5 of Herpes Simplex Virus Type 1 and Facilitates Viral Nuclear Egress

Wang

Yang

et al. 2014

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

“…To construct GFPp32, p32 coding region was obtained by PCR and cloned into the XhoI/BamHI site of pEGFP-C1 vector. The short hairpin RNA (shRNA) targeting p32 and a random sequence RNA were obtained from Xu et al (35). Oligonucleotides were synthesized and cloned into the AgeI/EcoRI site of pLKO.1 vector.…”

Section: Methodsmentioning

confidence: 99%

p32 Is a Novel Target for Viral Protein ICP34.5 of Herpes Simplex Virus Type 1 and Facilitates Viral Nuclear Egress

Wang

Yang

et al. 2014

Journal of Biological Chemistry

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“…Negative regulators, including NLRX1, SIKE, Atg5-Atg12, DAK, and CYLD, are constitutive or steady-state inhibitors of antiviral signaling, keeping aberrant IFN activation in check via mechanisms involving sequestration or competition (42)(43)(44)(45)(46). Other physiological regulators, such as RNF125, RNF5, Pin1, ISG15, ISG56, RBCK1, Ro52/TRIM21, gC1qR, DUBA, OTUB1/2, and optineurin, inhibit type I interferon production via negative feedback mechanisms (39,40,(47)(48)(49)(50)(51)(52)(53)(54)(55). A20 is one such physiological inhibitor of IFN; however, its mechanism of action has remained elusive.…”

Section: Discussionmentioning

confidence: 99%

TAX1BP1 and A20 Inhibit Antiviral Signaling by Targeting TBK1-IKKi Kinases

Parvatiyar

Barber

Harhaj

2010

Journal of Biological Chemistry

154

148

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Induction of type I interferons by the transcription factor IRF3 is essential in the initiation of antiviral innate immunity. Activation of IRF3 requires C-terminal phosphorylation by the upstream kinases TBK1-IKKi, where IRF3 phosphorylation promotes dimerization, and subsequent nuclear translocation to the IFN␤ promoter. Recent studies have described the ubiquitin-editing enzyme A20 as a negative regulator of IRF3 signaling by associating with TBK1-IKKi; however, the regulatory mechanism of A20 inhibition remains unclear. Here we describe the adaptor protein, TAX1BP1, as a key regulator of A20 function in terminating signaling to IRF3. Murine embryonic fibroblasts (MEFs) deficient in TAX1BP1 displayed increased amounts of IFN␤ production upon viral challenge compared with WT MEFs. TAX1BP1 inhibited virus-mediated activation of IRF3 at the level of TBK1-IKKi. TAX1BP1 and A20 blocked antiviral signaling by disrupting Lys 63 -linked polyubiquitination of TBK1-IKKi independently of the A20 deubiquitination domain. Furthermore, TAX1BP1 was required for A20 effector function because A20 was defective for the targeting and inactivation of TBK1 and IKKi in Tax1bp1 ؊/؊ MEFs. Additionally, we found the E3 ubiquitin ligase TRAF3 to play a critical role in promoting TBK1-IKKi ubiquitination. Collectively, our results demonstrate TBK1-IKKi to be novel substrates for A20 and further identify a novel mechanism whereby A20 and TAX1BP1 restrict antiviral signaling by disrupting a TRAF3-TBK1-IKKi signaling complex.

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“…Recently, ISGs such as ISG56, Optineurin, gC1qR, LGP2, and SARM were shown to negatively regulate the antiviral response by interfering with interactions between signaling components (12)(13)(14)(15)(16), whereas another group of ISGs, including ISG15, A20, RNF125, TRIAD3a, PCBP2, and Ro52, induce degradation of signaling factors via the ubiquitin-proteasome system (17)(18)(19)(20)(21)(22). Importantly, the physiological relevance of negative regulators is highlighted by the fact that many inflammatory diseases in humans, such as systemic lupus erythematosus and psoriasis, have been found to be associated with defects in the regulation of host IFN production (23).…”

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confidence: 99%

Interferon-Inducible Protein IFI35 Negatively Regulates RIG-I Antiviral Signaling and Supports Vesicular Stomatitis Virus Replication

Das

Dinh

Panda

et al. 2014

J Virol

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In a genome-wide small interfering RNA (siRNA) screen, we recently identified the interferon (IFN)-inducible protein 35 (IFI35; also known as IFP35) as a factor required for vesicular stomatitis virus (VSV) infection. Studies reported here were conducted to further understand the role and requirement of IFI35 in VSV infection. Consistent with the siRNA screening data, we found that depletion of IFI35 led to reduced VSV replication at the level of viral gene expression. Although no direct interaction of IFI35 with the viral replication machinery was observed, we found that IFI35 negatively regulated the host innate immune response and rescued poly(I·C)-induced inhibition of VSV replication. Promoter-driven reporter gene assays demonstrated that IFI35 overexpression suppressed the activation of IFN-␤ and ISG56 promoters, whereas its depletion had the opposite effect. Further investigation revealed that IFI35 specifically interacted with retinoic acid-inducible gene I (RIG-I) and negatively regulated its activation through mechanisms that included (i) suppression of dephosphorylation (activation) of RIG-I and (ii) proteasome-mediated degradation of RIG-I via K48-linked ubiquitination. Overall, the results presented here suggest a novel role for IFI35 in negative regulation of RIG-I-mediated antiviral signaling, which will have implications for diseases associated with excessive immune signaling. IMPORTANCE Mammalian cells employ a variety of mechanisms, including production of interferons (IFNs), to counteract invading pathogens. In this study, we identified a novel role for a cellular protein, IFN-inducible protein 35 (IFP35/IFI35), in negatively regulating the host IFN response during vesicular stomatitis virus (VSV) infection. Specifically, we found that IFI35 inhibited activation of the RNA sensor, the retinoic acid-inducible gene I (RIG-I), leading to inhibition of IFN production and thus resulting in better replication of VSV. The identification of a cellular factor that attenuates the IFN response will have implications toward understanding inflammatory diseases in humans that have been found to be associated with defects in the regulation of host IFN production, such as systemic lupus erythematosus and psoriasis.

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Inhibition of RIG-I and MDA5-dependent antiviral response by gC1qR at mitochondria

Cited by 128 publications

References 32 publications

p32 Is a Novel Target for Viral Protein ICP34.5 of Herpes Simplex Virus Type 1 and Facilitates Viral Nuclear Egress

p32 Is a Novel Target for Viral Protein ICP34.5 of Herpes Simplex Virus Type 1 and Facilitates Viral Nuclear Egress

TAX1BP1 and A20 Inhibit Antiviral Signaling by Targeting TBK1-IKKi Kinases

Interferon-Inducible Protein IFI35 Negatively Regulates RIG-I Antiviral Signaling and Supports Vesicular Stomatitis Virus Replication

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