Regulation of RLR-mediated innate immune signaling – It is all about keeping the balance

Eisenächer, Katharina; Krug, Anne

doi:10.1016/j.ejcb.2011.01.011

Cited by 103 publications

(79 citation statements)

References 113 publications

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“…IFI35 is an ISG and is induced in response to IFN-␣/␥ treatment (8,10). In contrast to the classical role of ISGs in combating virus infection, many ISGs are known to regulate the antiviral response through negative-feedback mechanisms (23,42). We considered the possibility that IFI35 is a negative regulator of antiviral responses and thereby may support VSV replication.…”

Section: Depletion Of Ifi35 Inhibits Vsv Replicationmentioning

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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Section: Depletion Of Ifi35 Inhibits Vsv Replicationmentioning

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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“…The phosphorylation of IRF3 and the subsequent nuclear import of IRF3 play vital roles in IFN activation (62). Taking this into consideration, it was examined whether individually expressed RNP subunits have an effect on levels of IRF3 phosphorylation (via the monitoring of phosphorylated Ser396 [p-IRF3] and total IRF3 [IRF3]).…”

Section: Partial Relocalization Of Rig-i Into the Nucleus At Late Stamentioning

confidence: 99%

Interactions between the Influenza A Virus RNA Polymerase Components and Retinoic Acid-Inducible Gene I

Chen

Sutton

et al. 2014

J Virol

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The influenza A virus genome possesses eight negative-strand RNA segments in the form of viral ribonucleoprotein particles (vRNPs) in association with the three viral RNA polymerase subunits (PB2, PB1, and PA) and the nucleoprotein (NP). Through interactions with multiple host factors, the RNP subunits play vital roles in replication, host adaptation, interspecies transmission, and pathogenicity. In order to gain insight into the potential roles of RNP subunits in the modulation of the host's innate immune response, the interactions of each RNP subunit with retinoic acid-inducible gene I protein (RIG-I) from mammalian and avian species were investigated. Studies using coimmunoprecipitation (co-IP), bimolecular fluorescence complementation (BiFc), and colocalization using confocal microscopy provided direct evidence for the RNA-independent binding of PB2, PB1, and PA with RIG-I from various hosts (human, swine, mouse, and duck). In contrast, the binding of NP with RIG-I was found to be RNA dependent. Influenza A virus is a member of the Orthomyxoviridae family and contains eight segments of negative-sense genomic RNA. Within the virus particle, viral RNAs (vRNAs) are wrapped with multiple copies of the nucleoprotein (NP) and are bound to a heterotrimeric polymerase complex composed of basic polymerases 1 and 2 (PB1 and PB2, respectively) and the acidic polymerase (PA) to collectively form viral ribonucleoprotein particles (vRNPs). Upon entry and uncoating, the vRNPs travel to the nucleus through interactions with importin-like factors and components of the nuclear pore complex. The vRNPs form the minimal units for transcription and replication of viral RNAs. PB2 recognizes and binds the methylated cap of cellular pre-mRNAs (1), and then PA cleaves the cap and generates 5=-capped RNA fragments (2), which are then used to prime viral mRNA transcription by PB1 (3). The accumulation of NP during infection is thought to favor the switching of viral RNA from transcription to replication (4) and promote the nuclear export of progeny vRNPs (in association with the viral proteins M1 and NEP and cellular factors) (5). The protein components of vRNPs are also involved in virulence, host adaptation, and interspecies transmission of influenza A virus, presumably due to interactions with numerous host factors (6).The innate immune response, especially the interferon (IFN)-mediated response, makes up the first line of defense against the invasion of pathogens. The production of type I IFN is primarily induced by Toll-like receptors (TLRs) located in the endosome or cellular membrane and RIG-I like receptors (RLRs) distributed mainly in the cytoplasm. RIG-I has been identified as the major cellular sensor for IFN induction upon influenza virus infection (7,8). RIG-I recognizes the 5= triphosphate (5=ppp) in viral genomic RNAs (9, 10) or double-stranded RNA (dsRNA) intermediates synthesized during virus replication (7, 11). Recently, RIG-I was shown to preferentially associate with short subgenomic viral segments in infe...

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“…Although type I IFN is critically required for viral clearance, aberrant type I IFN production (including IFN-α and IFN-β) can play a role in immunopathology and autoimmune disorders [11]. Thus, tight regulation of type I IFN signaling is critical to maintain homeostasis of both innate and adaptive immunity [12,13]. Ubiquitination is an important post-translational modification that plays a critical role in the positive or negative regulation of innate immune signaling pathways [14].…”

Section: Introductionmentioning

confidence: 99%

USP3 inhibits type I interferon signaling by deubiquitinating RIG-I-like receptors

et al. 2013

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Lysine 63 (K63)-linked ubiquitination of RIG-I plays a critical role in the activation of type I interferon pathway, yet the molecular mechanism responsible for its deubiquitination is still poorly understood. Here we report that the deubiquitination enzyme ubiquitin-specific protease 3 (USP3) negatively regulates the activation of type I interferon signaling by targeting RIG-I. Knockdown of USP3 specifically enhanced K63-linked ubiquitination of RIG-I, upregulated the phosphorylation of IRF3 and augmented the production of type I interferon cytokines and antiviral immunity. We further show that there is no interaction between USP3 and RIG-I-like receptors (RLRs) in unstimulated or uninfected cells, but upon viral infection or ligand stimulation, USP3 binds to the caspase activation recruitment domain of RLRs and then cleaves polyubiquitin chains through cooperation of its zinc-finger Ub-binding domain and USP catalytic domains. Mutation analysis reveals that binding of USP3 to polyubiquitin chains on RIG-I is a prerequisite step for its cleavage of polyubiquitin chains. Our findings identify a previously unrecognized role of USP3 in RIG-I activation and provide insights into the mechanisms by which USP3 inhibits RIG-I signaling and antiviral immunity.

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Regulation of RLR-mediated innate immune signaling – It is all about keeping the balance

Cited by 103 publications

References 113 publications

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

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

Interactions between the Influenza A Virus RNA Polymerase Components and Retinoic Acid-Inducible Gene I

USP3 inhibits type I interferon signaling by deubiquitinating RIG-I-like receptors

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