scholarly journals Transcriptional and Non-Transcriptional Activation, Posttranslational Modifications, and Antiviral Functions of Interferon Regulatory Factor 3 and Viral Antagonism by the SARS-Coronavirus

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 575
Author(s):  
Anna Glanz ◽  
Sukanya Chakravarty ◽  
Merina Varghese ◽  
Anita Kottapalli ◽  
Shumin Fan ◽  
...  
Keyword(s):  
Virus Infection ◽  
Posttranslational Modifications ◽  
Transcriptional Activation ◽  
Viral Infections ◽  
Interferon Regulatory Factor ◽  
Innate Immune ◽  
Type I ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 3 ◽  
Wide Range

The immune system defends against invading pathogens through the rapid activation of innate immune signaling pathways. Interferon regulatory factor 3 (IRF3) is a key transcription factor activated in response to virus infection and is largely responsible for establishing an antiviral state in the infected host. Studies in Irf3−/−mice have demonstrated the absence of IRF3 imparts a high degree of susceptibility to a wide range of viral infections. Virus infection causes the activation of IRF3 to transcribe type-I interferon (e.g., IFNβ), which is responsible for inducing the interferon-stimulated genes (ISGs), which act at specific stages to limit virus replication. In addition to its transcriptional function, IRF3 is also activated to trigger apoptosis of virus-infected cells, as a mechanism to restrict virus spread within the host, in a pathway called RIG-I-like receptor-induced IRF3 mediated pathway of apoptosis (RIPA). These dual functions of IRF3 work in concert to mediate protective immunity against virus infection. These two pathways are activated differentially by the posttranslational modifications (PTMs) of IRF3. Moreover, PTMs regulate not only IRF3 activation and function, but also protein stability. Consequently, many viruses utilize viral proteins or hijack cellular enzymes to inhibit IRF3 functions. This review will describe the PTMs that regulate IRF3′s RIPA and transcriptional activities and use coronavirus as a model virus capable of antagonizing IRF3-mediated innate immune responses. A thorough understanding of the cellular control of IRF3 and the mechanisms that viruses use to subvert this system is critical for developing novel therapies for virus-induced pathologies.

scholarly journals Bromodomain protein Brd3 promotes Ifnb1 transcription via enhancing IRF3/p300 complex formation and recruitment to Ifnb1 promoter in macrophages

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Wenhui Ren ◽  
Chunmei Wang ◽  
Qinlan Wang ◽  
Dezhi Zhao ◽  
Kai Zhao ◽  
...  
Keyword(s):  
Immune Response ◽  
Virus Infection ◽  
Innate Immune Response ◽  
Transcriptional Activation ◽  
Cell Cycle Progression ◽  
Innate Immune ◽  
Type I ◽  
Wide Range ◽  
Bromodomain Proteins ◽  
Protein Scaffolding

AbstractAs members of bromodomain and extra-terminal motif protein family, bromodomain-containing proteins regulate a wide range of biological processes including protein scaffolding, mitosis, cell cycle progression and transcriptional regulation. The function of these bromodomain proteins (Brds) in innate immune response has been reported but the role of Brd3 remains unclear. Here we find that virus infection significantly downregulate Brd3 expression in macrophages and Brd3 knockout inhibits virus-triggered IFN-β production. Brd3 interacts with both IRF3 and p300, increases p300-mediated acetylation of IRF3, and enhances the association of IRF3 with p300 upon virus infection. Importantly, Brd3 promotes the recruitment of IRF3/p300 complex to the promoter of Ifnb1, and increases the acetylation of histone3/histone4 within the Ifnb1 promoter, leading to the enhancement of type I interferon production. Therefore, our work indicated that Brd3 may act as a coactivator in IRF3/p300 transcriptional activation of Ifnb1 and provided new epigenetic mechanistic insight into the efficient activation of the innate immune response.

scholarly journals Vpu Mediates Depletion of Interferon Regulatory Factor 3 during HIV Infection by a Lysosome-Dependent Mechanism

2012 ◽  
Vol 86 (16) ◽  
pp. 8367-8374 ◽  
Author(s):  
Brian P. Doehle ◽  
Kristina Chang ◽  
Arjun Rustagi ◽  
John McNevin ◽  
M. Juliana McElrath ◽  
...  
Keyword(s):  
Immune Response ◽  
Hiv Infection ◽  
Interferon Regulatory Factor ◽  
Innate Immune ◽  
Productive Infection ◽  
Type I ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 3 ◽  
Antiviral Immune Response ◽  
Immune Defenses

HIV has evolved sophisticated mechanisms to avoid restriction by intracellular innate immune defenses that otherwise serve to control acute viral infection and virus dissemination. Innate defenses are triggered when pattern recognition receptor (PRR) proteins of the host cell engage pathogen-associated molecule patterns (PAMPs) present in viral products. Interferon regulatory factor 3 (IRF3) plays a central role in PRR signaling of innate immunity to drive the expression of type I interferon (IFN) and interferon-stimulated genes (ISGs), including a variety of HIV restriction factors, that serve to limit viral replication directly and/or program adaptive immunity. Productive infection of T cells by HIV is dependent upon the targeted proteolysis of IRF3 that occurs through a virus-directed mechanism that results in suppression of innate immune defenses. However, the mechanisms by which HIV controls innate immune signaling and IRF3 function are not defined. Here, we examined the innate immune response induced by HIV strains identified through their differential control of PRR signaling. We identified viruses that, unlike typical circulating HIV strains, lack the ability to degrade IRF3. Our studies show that IRF3 regulation maps specifically to the HIV accessory protein Vpu. We define a molecular interaction between Vpu and IRF3 that redirects IRF3 to the endolysosome for proteolytic degradation, thus allowing HIV to avoid the innate antiviral immune response. Our studies reveal that Vpu is an important IRF3 regulator that supports acute HIV infection through innate immune suppression. These observations define the Vpu-IRF3 interface as a novel target for therapeutic strategies aimed at enhancing the immune response to HIV.

scholarly journals Vaccinia Virus Expressing Interferon Regulatory Factor 3 Induces Higher Protective Immune Responses against Lethal Poxvirus Challenge in Atopic Organism

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1986
Author(s):  
Hana Pilna ◽  
Vera Hajkova ◽  
Jarmila Knitlova ◽  
Jana Liskova ◽  
Jana Elsterova ◽  
...  
Keyword(s):  
Immune Responses ◽  
Vaccinia Virus ◽  
Viral Infections ◽  
Type I Interferon ◽  
Lethal Dose ◽  
Interferon Regulatory Factor ◽  
Type I ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 3 ◽  
Virus Growth

Vaccinia virus (VACV) is an enveloped DNA virus from the Orthopoxvirus family, various strains of which were used in the successful eradication campaign against smallpox. Both original and newer VACV-based replicating vaccines reveal a risk of serious complications in atopic individuals. VACV encodes various factors interfering with host immune responses at multiple levels. In atopic skin, the production of type I interferon is compromised, while VACV specifically inhibits the phosphorylation of the Interferon Regulatory Factor 3 (IRF-3) and expression of interferons. To overcome this block, we generated a recombinant VACV-expressing murine IRF-3 (WR-IRF3) and characterized its effects on virus growth, cytokine expression and apoptosis in tissue cultures and in spontaneously atopic Nc/Nga and control Balb/c mice. Further, we explored the induction of protective immune responses against a lethal dose of wild-type WR, the surrogate of smallpox. We demonstrate that the overexpression of IRF-3 by WR-IRF3 increases the expression of type I interferon, modulates the expression of several cytokines and induces superior protective immune responses against a lethal poxvirus challenge in both Nc/Nga and Balb/c mice. Additionally, the results may be informative for design of other virus-based vaccines or for therapy of different viral infections.

scholarly journals Interferon regulatory factor 1 (IRF1) and anti-pathogen innate immune responses

2021 ◽  
Vol 17 (1) ◽  
pp. e1009220
Author(s):  
Hui Feng ◽  
Yi-Bing Zhang ◽  
Jian-Fang Gui ◽  
Stanley M. Lemon ◽  
Daisuke Yamane
Keyword(s):  
Interferon Regulatory Factor ◽  
Innate Immune ◽  
Fine Tuning ◽  
Type I ◽  
Innate Immune Responses ◽  
Host Defenses ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 1 ◽  
Wide Range ◽  
Range Of Functions

The eponymous member of the interferon regulatory factor (IRF) family, IRF1, was originally identified as a nuclear factor that binds and activates the promoters of type I interferon genes. However, subsequent studies using genetic knockouts or RNAi-mediated depletion of IRF1 provide a much broader view, linking IRF1 to a wide range of functions in protection against invading pathogens. Conserved throughout vertebrate evolution, IRF1 has been shown in recent years to mediate constitutive as well as inducible host defenses against a variety of viruses. Fine-tuning of these ancient IRF1-mediated host defenses, and countering strategies by pathogens to disarm IRF1, play crucial roles in pathogenesis and determining the outcome of infection.

scholarly journals Ipr1 Regulation by Cyclic GMP-AMP Synthase/Interferon Regulatory Factor 3 and Modulation of Irgm1 Expression via p53

2020 ◽  
Vol 40 (8) ◽  
Author(s):  
Fayang Liu ◽  
Hongni Xue ◽  
Jie Ke ◽  
Yongyan Wu ◽  
Kezhen Yao ◽  
...  
Keyword(s):  
Cyclic Gmp ◽  
Viral Infections ◽  
Pathogen Resistance ◽  
Interferon Regulatory Factor ◽  
Intracellular Pathogen ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 3 ◽  
Promoter Characterization ◽  
Ribosomal Protein L11 ◽  
Pathogenic Infection

ABSTRACT Intracellular pathogen resistance 1 (Ipr1) has been found to be a mediator to integrate cyclic GMP-AMP synthase (cGAS)–interferon regulatory factor 3 (IRF3), activated by intracellular pathogens, with the p53 pathway. Previous studies have shown the process of Ipr1 induction by various immune reactions, including intracellular bacterial and viral infections. The present study demonstrated that Ipr1 is regulated by the cGAS-IRF3 pathway during pathogenic infection. IRF3 was found to regulate Ipr1 expression by directly binding the interferon-stimulated response element motif of the Ipr1 promoter. Knockdown of Ipr1 decreased the expression of immunity-related GTPase family M member 1 (Irgm1), which plays critical roles in autophagy initiation. Irgm1 promoter characterization revealed a p53 motif in front of the transcription start site. P53 was found to participate in regulation of Irgm1 expression and IPR1-related effects on P53 stability by affecting interactions between ribosomal protein L11 (RPL11) and transformed mouse 3T3 cell double minute 2 (MDM2). Our results indicate that Ipr1 integrates cGAS-IRF3 with p53-modulated Irgm1 expression.

scholarly journals Identification of Feline Interferon Regulatory Factor 1 as an Efficient Antiviral Factor against the Replication of Feline Calicivirus and Other Feline Viruses

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Yongxiang Liu ◽  
Xiaoxiao Liu ◽  
Hongtao Kang ◽  
Xiaoliang Hu ◽  
Jiasen Liu ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Viral Infections ◽  
Interferon Regulatory Factor ◽  
Feline Calicivirus ◽  
Type I ◽  
Norwalk Virus ◽  
Regulatory Factor ◽  
Feline Panleukopenia Virus ◽  
Protein Levels ◽  
Interferon Regulatory Factor 1

Interferons (IFNs) can inhibit most, if not all, viral infections by eliciting the transcription of hundreds of interferon-stimulated genes (ISGs). Feline calicivirus (FCV) is a highly contagious pathogen of cats and a surrogate for Norwalk virus. Interferon efficiently inhibits the replication of FCV, but the mechanism of the antiviral activity is poorly understood. Here, we evaluated the anti-FCV activity of ten ISGs, whose antiviral activities were previously reported. The results showed that interferon regulatory factor 1 (IRF1) can significantly inhibit the replication of FCV, whereas the other ISGs tested in this study failed. Further, we found that IRF1 was localized in the nucleus and efficiently activated IFN-β and the ISRE promoter. IRF1 can trigger the production of endogenous interferon and the expression of ISGs, suggesting that IRF1 can positively regulate IFN signalling. Importantly, the mRNA and protein levels of IRF1 were reduced upon FCV infection, which may be a new strategy for FCV to evade the innate immune system. Finally, the antiviral activity of IRF1 against feline panleukopenia virus, feline herpesvirus, and feline infectious peritonitis virus was demonstrated. These data indicate that feline IRF1 plays an important role in regulating the host type I IFN response and inhibiting feline viral infections.

scholarly journals Oyster viperin retains direct antiviral activity and its transcription occurs via a signalling pathway involving a heat-stable haemolymph protein

2015 ◽  
Vol 96 (12) ◽  
pp. 3587-3597 ◽  
Author(s):  
Timothy J. Green ◽  
Peter Speck ◽  
Lu Geng ◽  
David Raftos ◽  
Michael R. Beard ◽  
...  
Keyword(s):  
Immune System ◽  
Virus Infection ◽  
Antiviral Activity ◽  
Innate Immune System ◽  
Innate Immune ◽  
Type I ◽  
Regulatory Factor ◽  
Antiviral Protein ◽  
Caveolin 1 ◽  
Heat Stable

Little is known about the response of non-model invertebrates, such as oysters, to virus infection. The vertebrate innate immune system detects virus-derived nucleic acids to trigger the type I IFN pathway, leading to the transcription of hundreds of IFN-stimulated genes (ISGs) that exert antiviral functions. Invertebrates were thought to lack the IFN pathway based on the absence of IFN or ISGs encoded in model invertebrate genomes. However, the oyster genome encodes many ISGs, including the well-described antiviral protein viperin. In this study, we characterized oyster viperin and showed that it localizes to caveolin-1 and inhibits dengue virus replication in a heterologous model. In a second set of experiments, we have provided evidence that the haemolymph from poly(I : C)-injected oysters contains a heat-stable, protease-susceptible factor that induces haemocyte transcription of viperin mRNA in conjunction with upregulation of IFN regulatory factor. Collectively, these results support the concept that oysters have antiviral systems that are homologous to the vertebrate IFN pathway.

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