NDR2 promotes the antiviral immune response via facilitating TRIM25-mediated RIG-I activation in macrophages

Retinoic acid–inducible gene I (RIG-I), a pivotal cytosolic sensor, recognizes viral RNAs to initiate antiviral innate immunity. However, posttranslational regulation of RIG-I signaling is not well understood. We report here that nuclear Dbf2-related kinase 2 (NDR2) functions as a crucial positive regulator of the RIG-I–mediated antiviral immune response. Overexpression of NDR2 or its kinase-inactive mutants potentiates RNA virus–induced production of type I interferons and proinflammatory cytokines and dampens viral replication. NDR2 conditional knockout mice (Lysm+NDR2f/f) show an impaired antiviral immune response. Mechanistically, NDR2 directly associates with RIG-I and TRIM25, thus facilitating the RIG-I/TRIM25 complex and enhancing the TRIM25-mediated K63-linked polyubiquitination of RIG-I, which is required for the RIG-I–mediated antiviral immune response. Furthermore, NDR2 expression is notably down-regulated in peripheral blood from respiratory syncytial virus–infected patients and in virus-infected macrophages. Collectively, these findings provide insights into the function of NDR2 in antiviral immunity and its related clinical significance.

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Inhibition of Antiviral Innate Immunity by Avibirnavirus VP3 via Blocking TBK1-TRAF3 Complex Formation and IRF3 Activation

mSystems ◽

10.1128/msystems.00016-21 ◽

2021 ◽

Vol 6 (3) ◽

Author(s):

Tingjuan Deng ◽

Boli Hu ◽

Xingbo Wang ◽

Lulu Lin ◽

Jianwei Zhou ◽

...

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Virus Infection ◽

Complex Formation ◽

Rna Virus ◽

Critical Role ◽

Type I ◽

Antiviral Immune Response ◽

Critical Residue ◽

Irf3 Activation

ABSTRACT The host innate immune system develops various strategies to antagonize virus infection, and the pathogen subverts or evades host innate immunity for self-replication. In the present study, we discovered that Avibirnavirus infectious bursal disease virus (IBDV) VP3 protein significantly inhibits MDA5-induced beta interferon (IFN-β) expression by blocking IRF3 activation. Binding domain mapping showed that the CC1 domain of VP3 and the residue lysine-155 of tumor necrosis factor receptor-associated factor 3 (TRAF3) are essential for the interaction. Furthermore, we found that the CC1 domain was required for VP3 to downregulate MDA5-mediated IFN-β production. A ubiquitination assay showed that lysine-155 of TRAF3 was the critical residue for K33-linked polyubiquitination, which contributes to the formation of a TRAF3-TBK1 complex. Subsequently, we revealed that VP3 blocked TRAF3-TBK1 complex formation through reducing K33-linked polyubiquitination of lysine-155 on TRAF3. Taken together, our data reveal that VP3 inhibits MDA5-dependent IRF3-mediated signaling via blocking TRAF3-TBK1 complex formation, which improves our understanding of the interplay between RNA virus infection and the innate host antiviral immune response. IMPORTANCE Type I interferon plays a critical role in the host response against virus infection, including Avibirnavirus. However, many viruses have developed multiple strategies to antagonize the innate host antiviral immune response during coevolution with the host. In this study, we first identified that K33-linked polyubiquitination of lysine-155 of TRAF3 enhances the interaction with TBK1, which positively regulates the host IFN immune response. Meanwhile, we discovered that the interaction of the CC1 domain of the Avibirnavirus VP3 protein and the residue lysine-155 of TRAF3 reduced the K33-linked polyubiquitination of TRAF3 and blocked the formation of the TRAF3-TBK1 complex, which contributed to the downregulation of host IFN signaling, supporting viral replication.

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MAVS Coordination of Antiviral Innate Immunity

Journal of Virology ◽

10.1128/jvi.01918-14 ◽

2015 ◽

Vol 89 (14) ◽

pp. 6974-6977 ◽

Cited By ~ 75

Author(s):

Christine Vazquez ◽

Stacy M. Horner

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Endoplasmic Reticulum ◽

Retinoic Acid ◽

Rna Virus ◽

Adaptor Protein ◽

Innate Immune ◽

Antiviral Signaling ◽

Antiviral Innate Immunity ◽

Inducible Gene

RNA virus infection is sensed in the cytoplasm by the retinoic acid-inducible gene I (RIG-I)-like receptors. These proteins signal through the host adaptor protein MAVS to trigger the antiviral innate immune response. Here, we describe how MAVS subcellular localization impacts its function and the regulation underlying MAVS signaling. We propose a model to describe how the coordination of MAVS functions at the interface between the mitochondria and the mitochondrion-associated endoplasmic reticulum (ER) membrane programs antiviral signaling.

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Fas-Associated Factor 1 Negatively Regulates the Antiviral Immune Response by Inhibiting Translocation of Interferon Regulatory Factor 3 to the Nucleus

Molecular and Cellular Biology ◽

10.1128/mcb.00744-15 ◽

2016 ◽

Vol 36 (7) ◽

pp. 1136-1151 ◽

Cited By ~ 12

Author(s):

Soonhwa Song ◽

Jae-Jin Lee ◽

Hee-Jung Kim ◽

Jeong Yoon Lee ◽

Jun Chang ◽

...

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Target Genes ◽

Nuclear Translocation ◽

Antiviral Response ◽

Innate Immune ◽

Type I Interferons ◽

Type I ◽

Antiviral Immune Response ◽

Associated Factor

This study is designed to examine the cellular functions of human Fas-associated factor 1 (FAF1) containing multiple ubiquitin-related domains. Microarray analyses revealed that interferon-stimulated genes related to the antiviral response are significantly increased in FAF1-knockdown HeLa cells. Silencing FAF1 enhanced the poly(I·C)- and respiratory syncytial virus (RSV)-induced production of type I interferons (IFNs), the target genes of interferon regulator factor 3 (IRF3). IRF3 is a key transcription factor in IFN-β signaling responsible for the host innate immune response. This study also found that FAF1 and IRF3 physically associate with IPO5/importin-β3 and that overexpression of FAF1 reduces the interaction between IRF3 and IPO5/importin-β3. These findings suggest that FAF1 negatively regulates IRF3-mediated IFN-β production and the antiviral innate immune response by regulating nuclear translocation of IRF3. We conclude that FAF1 plays a novel role in negatively regulating virus-induced IFN-β production and the antiviral response by inhibiting the translocation of active, phosphorylated IRF3 from the cytosol to the nucleus.

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KAT8 selectively inhibits antiviral immunity by acetylating IRF3

Journal of Experimental Medicine ◽

10.1084/jem.20181773 ◽

2019 ◽

Vol 216 (4) ◽

pp. 772-785 ◽

Cited By ~ 8

Author(s):

Wanwan Huai ◽

Xingguang Liu ◽

Chunmei Wang ◽

Yunkai Zhang ◽

Xi Chen ◽

...

Keyword(s):

Posttranslational Modifications ◽

Transcriptional Activity ◽

Critical Role ◽

Type I Interferons ◽

Type I ◽

Gene Promoters ◽

Innate Immune Responses ◽

Antiviral Immune Response ◽

Lysine Acetyltransferase ◽

Antiviral Innate Immunity

The transcription factor interferon regulatory factor 3 (IRF3) is essential for virus infection–triggered induction of type I interferons (IFN-I) and innate immune responses. IRF3 activity is tightly regulated by conventional posttranslational modifications (PTMs) such as phosphorylation and ubiquitination. Here, we identify an unconventional PTM of IRF3 that directly inhibits its transcriptional activity and attenuates antiviral immune response. We performed an RNA interference screen and found that lysine acetyltransferase 8 (KAT8), which is ubiquitously expressed in immune cells (particularly in macrophages), selectively inhibits RNA and DNA virus–triggered IFN-I production in macrophages and dendritic cells. KAT8 deficiency protects mice from viral challenge by enhancing IFN-I production. Mechanistically, KAT8 directly interacts with IRF3 and mediates IRF3 acetylation at lysine 359 via its MYST domain. KAT8 inhibits IRF3 recruitment to IFN-I gene promoters and decreases the transcriptional activity of IRF3. Our study reveals a critical role for KAT8 and IRF3 lysine acetylation in the suppression of antiviral innate immunity.

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A mutation in POLR3E impairs antiviral immune response and RNA polymerase III

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2009947117 ◽

2020 ◽

Vol 117 (36) ◽

pp. 22113-22121

Author(s):

Aravind Ramanathan ◽

Michael Weintraub ◽

Natalie Orlovetskie ◽

Raphael Serruya ◽

Dhivakar Mani ◽

...

Keyword(s):

Rna Polymerase ◽

Rna Virus ◽

Rna Polymerase Iii ◽

Innate Immune ◽

Type I Interferons ◽

Homozygous Mutation ◽

Type I ◽

Protein Subunit ◽

Antiviral Immune Response ◽

Pol Iii

RNA polymerase (Pol) III has a noncanonical role of viral DNA sensing in the innate immune system. This polymerase transcribes viral genomes to produce RNAs that lead to induction of type I interferons (IFNs). However, the genetic and functional links of Pol III to innate immunity in humans remain largely unknown. Here, we describe a rare homozygous mutation (D40H) in the POLR3E gene, coding for a protein subunit of Pol III, in a child with recurrent and systemic viral infections and Langerhans cell histiocytosis. Fibroblasts derived from the patient exhibit impaired induction of type I IFN and increased susceptibility to human cytomegalovirus (HCMV) infection. Cultured cell lines infected with HCMV show induction of POLR3E expression. However, induction is not restricted to DNA virus, as sindbis virus, an RNA virus, enhances the expression of this protein. Likewise, foreign nonviral DNA elevates the steady-state level of POLR3E and elicits promoter-dependent and -independent transcription by Pol III. Remarkably, the molecular mechanism underlying the D40H mutation of POLR3E involves the assembly of defective initiation complexes of Pol III. Our study links mutated POLR3E and Pol III to an innate immune deficiency state in humans.

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Type I Interferons in COVID-19 Pathogenesis

Biology ◽

10.3390/biology10090829 ◽

2021 ◽

Vol 10 (9) ◽

pp. 829

Author(s):

Enrico Palermo ◽

Daniele Di Carlo ◽

Marco Sgarbanti ◽

John Hiscott

Keyword(s):

Immune Response ◽

Genetic Basis ◽

Type I Interferons ◽

Type I ◽

Virus Propagation ◽

Antiviral Immune Response ◽

The Many ◽

Host Virus Interactions ◽

Virus Interactions

Among the many activities attributed to the type I interferon (IFN) multigene family, their roles as mediators of the antiviral immune response have emerged as important components of the host response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Viruses likewise have evolved multiple immune evasion strategies to circumvent the host immune response and promote virus propagation and dissemination. Therefore, a thorough characterization of host–virus interactions is essential to understand SARS-CoV-2 pathogenesis. Here, we summarize the virus-mediated evasion of the IFN responses and the viral functions involved, the genetic basis of IFN production in SARS-CoV-2 infection and the progress of clinical trials designed to utilize type I IFN as a potential therapeutic tool.

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Interferon-Inducible LINC02605 Promotes Antiviral Innate Responses by Strengthening IRF3 Nuclear Translocation

Frontiers in Immunology ◽

10.3389/fimmu.2021.755512 ◽

2021 ◽

Vol 12 ◽

Author(s):

Rui Xu ◽

Shuang-Shuang Yu ◽

Ran-Ran Yao ◽

Rong-Chun Tang ◽

Jia-Wei Liang ◽

...

Keyword(s):

Immune Response ◽

Viral Replication ◽

Innate Immune Response ◽

Nuclear Translocation ◽

Rna Virus ◽

Innate Immune ◽

Pten Expression ◽

Type I ◽

Dependent Manner ◽

Antiviral Immune Response

Non-coding RNAs represent a class of important regulators in immune response. Previously, LINC02605 was identified as a candidate regulator in innate immune response by lncRNA microarray assays. In this study, we systematically analyzed the functions and the acting mechanisms of LINC02605 in antiviral innate immune response. LINC02605 was up-regulated by RNA virus, DNA virus, and type I IFNs in NF-κB and Jak-stat dependent manner. Overexpression of LINC02605 promotes RNA virus-induced type I interferon production and inhibited viral replication. Consistently, knockdown of LINC02605 resulted in reduced antiviral immune response and increased viral replication. Mechanistically, LINC02605 released the inhibition of hsa-miR-107 on the expression of phosphatase and tensin homolog (PTEN). By microRNA mimics and inhibitors, hsa-miR-107 was demonstrated to not only inhibit PTEN’s expression but also negatively regulate the antiviral immune response. Knockdown of LINC02605 led to the reduction of PTEN expression both in mRNA and protein levels. Overexpression of LINC02605 had an opposite impact. Moreover, LINC02605 attenuated the serine 97 phosphorylation level of interferon regulatory factor 3 (IRF3) by promoting PTEN expression. Nucleoplasmic fragmentation assay showed that knocking down LINC02605 inhibited the nuclear translocation of IRF3, rendering the host cells more susceptible to viral invasion, while overexpression showed opposite effects. Therefore, LINC02605 is an induced lncRNA by viral infection and plays a positive feedback in antiviral immune response through modulating the nuclear translocation of IRF3.

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Mutation in Irf8 Gene (Irf8R294C) Impairs Type I IFN-Mediated Antiviral Immune Response by Murine pDCs

Frontiers in Immunology ◽

10.3389/fimmu.2021.758190 ◽

2021 ◽

Vol 12 ◽

Author(s):

Annesa Das ◽

Kuldeep Singh Chauhan ◽

Himanshu Kumar ◽

Prafullakumar Tailor

Keyword(s):

Immune Response ◽

Point Mutation ◽

Single Point ◽

Costimulatory Molecules ◽

Type I Interferons ◽

Single Point Mutation ◽

Type I ◽

Type I Ifn ◽

Antiviral Immune Response

Plasmacytoid dendritic cells (pDCs) are the key producers of type I interferons (IFNs), thus playing a central role in initiating antiviral immune response. Besides robust type I IFN production, pDCs also act as antigen presenting cells post immunogenic stimulation. Transcription factor Irf8 is indispensable for the development of both pDC and cDC1 subset. However, the mechanism underlying the differential regulation by IRF8 in cDC1- and pDC-specific genomic architecture of developmental pathways still remains to be fully elucidated. Previous studies indicated that the Irf8R294C mutation specifically abrogates development of cDC1 without affecting that of pDC. In the present study using RNA-seq based approach, we have found that though the point mutation Irf8R294C did not affect pDC development, it led to defective type I IFN production, thus resulting in inefficient antiviral response. This observation unraveled the distinctive roles of IRF8 in these two subpopulations—regulating the development of cDC1 whereas modulating the functionality of pDCs without affecting development. We have reported here that Irf8R294C mutation also caused defect in production of ISGs as well as defective upregulation of costimulatory molecules in pDCs in response to NDV infection (or CpG stimulation). Through in vivo studies, we demonstrated that abrogation of type I IFN production was concomitant with reduced upregulation of costimulatory molecules in pDCs and increased NDV burden in IRF8R294C mice in comparison with wild type, indicating inefficient viral clearance. Further, we have also shown that Irf8R294C mutation abolished the activation of type I IFN promoter by IRF8, justifying the low level of type I IFN production. Taken together, our study signifies that the single point mutation in Irf8, Irf8R294C severely compromised type I IFN-mediated immune response by murine pDCs, thereby causing impairment in antiviral immunity.

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Bacterial Cyclic Dinucleotides and the cGAS–cGAMP–STING Pathway: A Role in Periodontitis?

Pathogens ◽

10.3390/pathogens10060675 ◽

2021 ◽

Vol 10 (6) ◽

pp. 675

Author(s):

Samira Elmanfi ◽

Mustafa Yilmaz ◽

Wilson W. S. Ong ◽

Kofi S. Yeboah ◽

Herman O. Sintim ◽

...

Keyword(s):

Immune Response ◽

Periodontal Disease ◽

Innate Immune ◽

Host Cells ◽

Type I Interferons ◽

Type I ◽

Vaccine Adjuvants ◽

Cyclic Dinucleotides ◽

Sting Pathway

Host cells can recognize cytosolic double-stranded DNAs and endogenous second messengers as cyclic dinucleotides—including c-di-GMP, c-di-AMP, and cGAMP—of invading microbes via the critical and essential innate immune signaling adaptor molecule known as STING. This recognition activates the innate immune system and leads to the production of Type I interferons and proinflammatory cytokines. In this review, we (1) focus on the possible role of bacterial cyclic dinucleotides and the STING/TBK1/IRF3 pathway in the pathogenesis of periodontal disease and the regulation of periodontal immune response, and (2) review and discuss activators and inhibitors of the STING pathway as immune response regulators and their potential utility in the treatment of periodontitis. PubMed/Medline, Scopus, and Web of Science were searched with the terms “STING”, “TBK 1”, “IRF3”, and “cGAS”—alone, or together with “periodontitis”. Current studies produced evidence for using STING-pathway-targeting molecules as part of anticancer therapy, and as vaccine adjuvants against microbial infections; however, the role of the STING/TBK1/IRF3 pathway in periodontal disease pathogenesis is still undiscovered. Understanding the stimulation of the innate immune response by cyclic dinucleotides opens a new approach to host modulation therapies in periodontology.

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