scholarly journals Regulated Nuclear-Cytoplasmic Localization of Interferon Regulatory Factor 3, a Subunit of Double-Stranded RNA-Activated Factor 1

2000 ◽  
Vol 20 (11) ◽  
pp. 4159-4168 ◽  
Author(s):  
K. Prasanna Kumar ◽  
Kevin M. McBride ◽  
Brian K. Weaver ◽  
Colin Dingwall ◽  
Nancy C. Reich
Keyword(s):  
Transcription Factor ◽  
Nuclear Localization ◽  
Nuclear Export ◽  
Interferon Regulatory Factor ◽  
Nuclear Accumulation ◽  
Type I ◽  
Cytoplasmic Localization ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 3 ◽  
Double Stranded Rna

ABSTRACT Viral double-stranded RNA (dsRNA) generated during the course of infection leads to the activation of a latent transcription factor, dsRNA-activated factor 1 (DRAF1). DRAF1 binds to a DNA target containing the type I interferon-stimulated response element and induces transcription of responsive genes. DRAF1 is a multimeric transcription factor containing the interferon regulatory factor 3 (IRF-3) protein and one of the histone acetyl transferases, CREB binding protein (CBP) or p300 (CBP/p300). In uninfected cells, the IRF-3 component of DRAF1 resides in the cytoplasm. The cytoplasmic localization of IRF-3 is dependent on a nuclear export signal, and we demonstrate IRF-3 recognition by the chromosome region maintenance 1 (CRM1) (also known as exportin 1) shuttling receptor. Following infection and specific phosphorylation, IRF-3 accumulates in the nucleus where it associates with CBP and p300. We identify a nuclear localization signal (NLS) in IRF-3 that is critical for nuclear accumulation. Mutation of the NLS abrogates nuclear localization even following infection. The NLS appears to be active constitutively, but it is recognized by only a subset of importin-α shuttling receptors. Evidence is presented to support a model in which IRF-3 normally shuttles between the nucleus and the cytoplasm but cytoplasmic localization is dominant prior to infection. Following infection, phosphorylated IRF-3 can bind to the CBP/p300 proteins resident in the nucleus. We provide the evidence of a role for CBP/p300 binding in the nuclear sequestration of a transcription factor that normally resides in the cytoplasm.

scholarly journals SARS-CoV-2 Spike Antagonizes Innate Antiviral Immunity by Targeting Interferon Regulatory Factor 3

2022 ◽  
Vol 11 ◽  
Author(s):  
Raul S. Freitas ◽  
Tyler F. Crum ◽  
Kislay Parvatiyar
Keyword(s):  
Immune Response ◽  
Transcription Factor ◽  
Virus Disease ◽  
Ectopic Expression ◽  
Interferon Regulatory Factor ◽  
Type I ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 3 ◽  
Antiviral Immune Response ◽  
Corona Virus

Corona virus disease 2019 (COVID-19) pathogenesis is intimately linked to the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) and disease severity has been associated with compromised induction of type I interferon (IFN-I) cytokines which coordinate the innate immune response to virus infections. Here we identified the SARS-CoV-2 encoded protein, Spike, as an inhibitor of IFN-I that antagonizes viral RNA pattern recognition receptor RIG-I signaling. Ectopic expression of SARS-CoV-2 Spike blocked RIG-I mediated activation of IFNβ and downstream induction of interferon stimulated genes. Consequently, SARS-CoV-2 Spike expressing cells harbored increased RNA viral burden compared to control cells. Co-immunoprecipitation experiments revealed SARS-CoV-2 Spike associated with interferon regulatory factor 3 (IRF3), a key transcription factor that governs IFN-I activation. Co-expression analysis via immunoassays further indicated Spike specifically suppressed IRF3 expression as NF-κB and STAT1 transcription factor levels remained intact. Further biochemical experiments uncovered SARS-CoV-2 Spike potentiated proteasomal degradation of IRF3, implicating a novel mechanism by which SARS-CoV-2 evades the host innate antiviral immune response to facilitate COVID-19 pathogenesis.

scholarly journals Regulation of Type I Interferon Gene Expression by Interferon Regulatory Factor-3

1998 ◽  
Vol 273 (5) ◽  
pp. 2714-2720 ◽  
Author(s):  
Susan L. Schafer ◽  
Rongtuan Lin ◽  
Paul A. Moore ◽  
John Hiscott ◽  
Paula M. Pitha
Keyword(s):  
Gene Expression ◽  
Type I Interferon ◽  
Interferon Regulatory Factor ◽  
Type I ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 3 ◽  
Interferon Gene

scholarly journals Positive Regulation of Interferon Regulatory Factor 3 Activation by Herc5 via ISG15 Modification

2010 ◽  
Vol 30 (10) ◽  
pp. 2424-2436 ◽  
Author(s):  
He-Xin Shi ◽  
Kai Yang ◽  
Xing Liu ◽  
Xin-Yi Liu ◽  
Bo Wei ◽  
...  
Keyword(s):  
Sendai Virus ◽  
Specific Binding ◽  
Ectopic Expression ◽  
Interferon Regulatory Factor ◽  
Type I Interferons ◽  
Type I ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 3 ◽  
Antiviral Responses ◽  
Irf3 Activation

ABSTRACT Virus infection induces host antiviral responses, including induction of type I interferons. Transcription factor interferon regulatory factor 3 (IRF3) plays a pivotal role and is tightly regulated in this process. Here, we identify HERC5 (HECT domain and RLD 5) as a specific binding protein of IRF3 by immunoprecipitation. Ectopic expression or knockdown of HERC5 could, respectively, enhance or impair IRF3-mediated gene expression. Mechanistically, HERC5 catalyzes the conjugation of ubiquitin-like protein ISG15 onto IRF3 (Lys193, -360, and -366), thus attenuating the interaction between Pin1 and IRF3, resulting in sustained IRF3 activation. In contrast to results for wild-type IRF3, the mutant IRF3(K193,360,366R) interacts tightly with Pin1, is highly polyubiquitinated, and becomes less stable upon Sendai virus (SeV) infection. Consistently, host antiviral responses are obviously boosted or crippled in the presence or absence of HERC5, respectively. Collectively, this study characterizes HERC5 as a positive regulator of innate antiviral responses. It sustains IRF3 activation via a novel posttranslational modification, ISGylation.

scholarly journals The 3C Protein of Enterovirus 71 Inhibits Retinoid Acid-Inducible Gene I-Mediated Interferon Regulatory Factor 3 Activation and Type I Interferon Responses

2010 ◽  
Vol 84 (16) ◽  
pp. 8051-8061 ◽  
Author(s):  
Xiaobo Lei ◽  
Xinlei Liu ◽  
Yijie Ma ◽  
Zhenmin Sun ◽  
Yaowu Yang ◽  
...  
Keyword(s):  
Rna Binding ◽  
Type I Interferon ◽  
Critical Role ◽  
Enterovirus 71 ◽  
Interferon Regulatory Factor ◽  
Type I ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 3 ◽  
Retinoid Acid ◽  
Inducible Gene

ABSTRACT Enterovirus 71 (EV71) is a human pathogen that induces hand, foot, and mouth disease and fatal neurological diseases. Immature or impaired immunity is thought to associate with increased morbidity and mortality. In a murine model, EV71 does not facilitate the production of type I interferon (IFN) that plays a critical role in the first-line defense against viral infection. Administration of a neutralizing antibody to IFN-α/β exacerbates the virus-induced disease. However, the molecular events governing this process remain elusive. Here, we report that EV71 suppresses the induction of antiviral immunity by targeting the cytosolic receptor retinoid acid-inducible gene I (RIG-I). In infected cells, EV71 inhibits the expression of IFN-β, IFN-stimulated gene 54 (ISG54), ISG56, and tumor necrosis factor alpha. Among structural and nonstructural proteins encoded by EV71, the 3C protein is capable of inhibiting IFN-β activation by virus and RIG-I. Nevertheless, EV71 3C exhibits no inhibitory activity on MDA5. Remarkably, when expressed in mammalian cells, EV71 3C associates with RIG-I via the caspase recruitment domain. This precludes the recruitment of an adaptor IPS-1 by RIG-I and subsequent nuclear translocation of interferon regulatory factor 3. An R84Q or V154S substitution in the RNA binding motifs has no effect. An H40D substitution is detrimental, but the protease activity associated with 3C is dispensable. Together, these results suggest that inhibition of RIG-I-mediated type I IFN responses by the 3C protein may contribute to the pathogenesis of EV71 infection.

scholarly journals The Lyme Disease Spirochete Borrelia burgdorferi Utilizes Multiple Ligands, Including RNA, for Interferon Regulatory Factor 3-Dependent Induction of Type I Interferon-Responsive Genes

2010 ◽  
Vol 78 (7) ◽  
pp. 3144-3153 ◽  
Author(s):  
Jennifer C. Miller ◽  
Heather Maylor-Hagen ◽  
Ying Ma ◽  
John H. Weis ◽  
Janis J. Weis
Keyword(s):  
Borrelia Burgdorferi ◽  
Gene Transcription ◽  
Type I Interferon ◽  
Interferon Regulatory Factor ◽  
Lyme Arthritis ◽  
Type I ◽  
Type I Ifn ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 3 ◽  
Responsive Gene

ABSTRACT We recently discovered a critical role for type I interferon (IFN) in the development of murine Lyme arthritis. Borrelia burgdorferi-mediated induction of IFN-responsive genes by bone marrow-derived macrophages (BMDMs) was dependent upon a functional type I IFN receptor but independent of Toll-like receptor 2 (TLR2), TLR4, TLR9, and the adapter molecule MyD88. We now demonstrate that induction of the IFN transcriptional profile in B. burgdorferi-stimulated BMDMs occurs independently of the adapter TRIF and of the cytoplasmic sensor NOD2. In contrast, B. burgdorferi-induced transcription of these genes was dependent upon a rapid STAT1 feedback amplification pathway. IFN profile gene transcription was IRF3 dependent but did not utilize B. burgdorferi-derived DNA or DNase-sensitive ligands. Instead, IFN-responsive gene expression could be induced by B. burgdorferi-derived RNA. Interferon regulatory factor 3 (IRF3)-dependent IFN profile gene transcription was also induced by sonicated bacteria, by the lipoprotein OspA, and by factors released into the BSKII medium during culture of B. burgdorferi. The IFN-stimulatory activity of B. burgdorferi culture supernatants was not destroyed by nuclease treatment. Nuclease digestion also had no effect on IFN profile induction mediated by sonicated B. burgdorferi. Thus, B. burgdorferi-derived RNA, OspA, and non-nucleic acid ligands present in both sonicated bacteria and B. burgdorferi culture medium contribute to type I IFN-responsive gene induction. These findings suggest that B. burgdorferi invasion of joint tissue and the resultant type I IFN induction associated with Lyme arthritis development may involve multiple triggering ligands.

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