scholarly journals TAX1BP1 Restrains Virus-Induced Apoptosis by Facilitating Itch-Mediated Degradation of the Mitochondrial Adaptor MAVS

2016 ◽  
Vol 37 (1) ◽  
Author(s):  
Young Bong Choi ◽  
Noula Shembade ◽  
Kislay Parvatiyar ◽  
Siddharth Balachandran ◽  
Edward William Harhaj
Keyword(s):  
Virus Infection ◽  
Sendai Virus ◽  
Apoptotic Cell ◽  
Rna Virus ◽  
Adaptor Protein ◽  
Negative Regulator ◽  
Type I ◽  
Adaptor Molecule ◽  
Highly Sensitive ◽  
Induced Apoptosis

ABSTRACTThe host response to RNA virus infection consists of an intrinsic innate immune response and the induction of apoptosis as mechanisms to restrict viral replication. The mitochondrial adaptor molecule MAVS plays critical roles in coordinating both virus-induced type I interferon production and apoptosis; however, the regulation of MAVS-mediated apoptosis is poorly understood. Here, we show that the adaptor protein TAX1BP1 functions as a negative regulator of virus-induced apoptosis. TAX1BP1-deficient cells are highly sensitive to apoptosis in response to infection with the RNA viruses vesicular stomatitis virus and Sendai virus and to transfection with poly(I·C). TAX1BP1 undergoes degradation during RNA virus infection, and loss of TAX1BP1 is associated with apoptotic cell death. TAX1BP1 deficiency augments virus-induced activation of proapoptotic c-Jun N-terminal kinase (JNK) signaling. Virus infection promotes the mitochondrial localization of TAX1BP1 and concomitant interaction with the mitochondrial adaptor MAVS. TAX1BP1 recruits the E3 ligase Itch to MAVS to trigger its ubiquitination and degradation, and loss of TAX1BP1 or Itch results in increased MAVS protein expression. Together, these results indicate that TAX1BP1 functions as an adaptor molecule for Itch to target MAVS during RNA virus infection and thus restrict virus-induced apoptosis.

scholarly journals Phosphatase Cdc25A Negatively Regulates the Antiviral Immune Response by Inhibiting TBK1 Activity

2018 ◽  
Vol 92 (19) ◽  
Author(s):  
Dandan Qi ◽  
Lei Hu ◽  
Tong Jiao ◽  
Tinghong Zhang ◽  
Xiaomei Tong ◽  
...  
Keyword(s):  
Immune Response ◽  
Virus Infection ◽  
Phosphatase Activity ◽  
Signaling Pathway ◽  
Sendai Virus ◽  
Rna Virus ◽  
Negative Regulator ◽  
Luciferase Assay ◽  
Dna Virus ◽  
Antiviral Immune Response

ABSTRACT The phosphatase Cdc25A plays an important role in cell cycle regulation by dephosphorylating its substrates, such as cyclin-dependent kinases. In this study, we demonstrate that Cdc25A negatively regulates RIG-I-mediated antiviral signaling. We found that ectopic expression of Cdc25A in 293T cells inhibits the activation of beta interferon (IFN-β) induced by Sendai virus and poly(I·C), while knockdown of Cdc25A enhances the transcription of IFN-β stimulated by RNA virus infection. The inhibitory effect of Cdc25A on the antiviral immune response is mainly dependent on its phosphatase activity. Data from a luciferase assay indicated that Cdc25A can inhibit TBK1-mediated activation of IFN-β. Further analysis indicated that Cdc25A can interact with TBK1 and reduce the phosphorylation of TBK1 at S172, which in turn decreases the phosphorylation of its downstream substrate IRF3. Consistently, knockdown of Cdc25A upregulates the phosphorylation of both TBK1-S172 and IRF3 in Sendai virus-infected or TBK1-transfected 293T cells. In addition, we confirmed that Cdc25A can directly dephosphorylate TBK1-S172-p. These results demonstrate that Cdc25A inhibits the antiviral immune response by reducing the active form of TBK1. Using herpes simplex virus 1 (HSV-1) infection, an IFN-β reporter assay, and reverse transcription-quantitative PCR (RT-qPCR), we demonstrated that Cdc25A can also inhibit DNA virus-induced activation of IFN-β. Using a vesicular stomatitis virus (VSV) infection assay, we confirmed that Cdc25A can repress the RIG-I-like receptor (RLR)-mediated antiviral immune response and influence the antiviral status of cells. In conclusion, we demonstrate that Cdc25A negatively regulates the antiviral immune response by inhibiting TBK1 activity. IMPORTANCE The RLR-mediated antiviral immune response is critical for host defense against RNA virus infection. However, the detailed mechanism for balancing the RLR signaling pathway in host cells is not well understood. We found that the phosphatase Cdc25A negatively regulates the RNA virus-induced innate immune response. Our studies indicate that Cdc25A inhibits the RLR signaling pathway via its phosphatase activity. We demonstrated that Cdc25A reduces TBK1 activity and consequently restrains the activation of IFN-β transcription as well as the antiviral status of nearby cells. We showed that Cdc25A can also inhibit DNA virus-induced activation of IFN-β. Taken together, our findings uncover a novel function and mechanism for Cdc25A in regulating antiviral immune signaling. These findings reveal Cdc25A as an important negative regulator of antiviral immunity and demonstrate its role in maintaining host cell homeostasis following viral infection.

scholarly journals JMJD6 negatively regulates cytosolic RNA induced antiviral signaling by recruiting RNF5 to promote activated IRF3 K48 ubiquitination

2021 ◽  
Vol 17 (3) ◽  
pp. e1009366
Author(s):  
Wei Zhang ◽  
Qi Wang ◽  
Fan Yang ◽  
Zixiang Zhu ◽  
Yueyue Duan ◽  
...  
Keyword(s):  
Immune Responses ◽  
Type I Interferon ◽  
Sendai Virus ◽  
Rna Virus ◽  
Negative Regulator ◽  
Viral Rna ◽  
Poly I:C ◽  
Type I ◽  
Dependent Manner ◽  
Antiviral Signaling

The negative regulation of antiviral immune responses is essential for the host to maintain homeostasis. Jumonji domain-containing protein 6 (JMJD6) was previously identified with a number of functions during RNA virus infection. Upon viral RNA recognition, retinoic acid-inducible gene-I-like receptors (RLRs) physically interact with the mitochondrial antiviral signaling protein (MAVS) and activate TANK-binding kinase 1 (TBK1) to induce type-I interferon (IFN-I) production. Here, JMJD6 was demonstrated to reduce type-I interferon (IFN-I) production in response to cytosolic poly (I:C) and RNA virus infections, including Sendai virus (SeV) and Vesicular stomatitis virus (VSV). Genetic inactivation of JMJD6 enhanced IFN-I production and impaired viral replication. Our unbiased proteomic screen demonstrated JMJD6 contributes to IRF3 K48 ubiquitination degradation in an RNF5-dependent manner. Mice with gene deletion of JMJD6 through piggyBac transposon-mediated gene transfer showed increased VSV-triggered IFN-I production and reduced susceptibility to the virus. These findings classify JMJD6 as a negative regulator of the host’s innate immune responses to cytosolic viral RNA.

scholarly journals Spatiotemporal dynamics of innate immune signaling via RIG-I–like receptors

2020 ◽  
Vol 117 (27) ◽  
pp. 15778-15788 ◽  
Author(s):  
Katharina Esser-Nobis ◽  
Lauren D. Hatfield ◽  
Michael Gale
Keyword(s):  
Innate Immunity ◽  
Virus Infection ◽  
Rna Virus ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Negative Regulator ◽  
Resting Cells ◽  
Immune Signaling ◽  
Innate Immune Signaling ◽  
Irf3 Activation

RIG-I, MDA5, and LGP2 comprise the RIG-I–like receptors (RLRs). RIG-I and MDA5 are essential pathogen recognition receptors sensing viral infections while LGP2 has been described as both RLR cofactor and negative regulator. After sensing and binding to viral RNA, including double-stranded RNA (dsRNA), RIG-I and MDA5 undergo cytosol-to-membrane relocalization to bind and signal through the MAVS adaptor protein on intracellular membranes, thus directing downstream activation of IRF3 and innate immunity. Here, we report examination of the dynamic subcellular localization of all three RLRs within the intracellular response to dsRNA and RNA virus infection. Observations from high resolution biochemical fractionation and electron microscopy, coupled with analysis of protein interactions and IRF3 activation, show that, in resting cells, microsome but not mitochondrial fractions harbor the central components to initiate innate immune signaling. LGP2 interacts with MAVS in microsomes, blocking the RIG-I/MAVS interaction. Remarkably, in response to dsRNA treatment or RNA virus infection, LGP2 is rapidly released from MAVS and redistributed to mitochondria, temporally correlating with IRF3 activation. We reveal that IRF3 activation does not take place on mitochondria but instead occurs at endoplasmic reticulum (ER)-derived membranes. Our observations suggest ER-derived membranes as key RLR signaling platforms controlled through inhibitory actions of LGP2 binding to MAVS wherein LGP2 translocation to mitochondria releases MAVS inhibition to facilitate RLR-mediated signaling of innate immunity.

scholarly journals USP18 positively regulates innate antiviral immunity by promoting K63-linked polyubiquitination of MAVS

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jinxiu Hou ◽  
Lulu Han ◽  
Ze Zhao ◽  
Huiqing Liu ◽  
Lei Zhang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Sendai Virus ◽  
Rna Virus ◽  
Antiviral Immunity ◽  
Encephalomyocarditis Virus ◽  
Type I ◽  
Antiviral Signaling ◽  
Central Function ◽  
Adaptor Molecule ◽  
Innate Antiviral Immunity

AbstractActivation of MAVS, an adaptor molecule in Rig-I-like receptor (RLR) signaling, is indispensable for antiviral immunity, yet the molecular mechanisms modulating MAVS activation are not completely understood. Ubiquitination has a central function in regulating the activity of MAVS. Here, we demonstrate that a mitochondria-localized deubiquitinase USP18 specifically interacts with MAVS, promotes K63-linked polyubiquitination and subsequent aggregation of MAVS. USP18 upregulates the expression and production of type I interferon following infection with Sendai virus (SeV) or Encephalomyocarditis virus (EMCV). Mice with a deficiency of USP18 are more susceptible to RNA virus infection. USP18 functions as a scaffold protein to facilitate the re-localization of TRIM31 and enhances the interaction between TRIM31 and MAVS in mitochondria. Our results indicate that USP18 functions as a post-translational modulator of MAVS-mediated antiviral signaling.

scholarly journals Cyclophilin A-regulated ubiquitination is critical for RIG-I-mediated antiviral immune responses

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Wei Liu ◽  
Jing Li ◽  
Weinan Zheng ◽  
Yingli Shang ◽  
Zhendong Zhao ◽  
...  
Keyword(s):  
Virus Infection ◽  
Immune Responses ◽  
Ubiquitin Ligase ◽  
Sendai Virus ◽  
Rna Virus ◽  
Cyclophilin A ◽  
Type I Interferons ◽  
Type I ◽  
Recognition Receptor

RIG-I is a key cytosolic pattern recognition receptor that interacts with MAVS to induce type I interferons (IFNs) against RNA virus infection. In this study, we found that cyclophilin A (CypA), a peptidyl-prolyl cis/trans isomerase, functioned as a critical positive regulator of RIG-I-mediated antiviral immune responses. Deficiency of CypA impaired RIG-I-mediated type I IFN production and promoted viral replication in human cells and mice. Upon Sendai virus infection, CypA increased the interaction between RIG-I and its E3 ubiquitin ligase TRIM25, leading to enhanced TRIM25-mediated K63-linked ubiquitination of RIG-I that facilitated recruitment of RIG-I to MAVS. In addition, CypA and TRIM25 competitively interacted with MAVS, thereby inhibiting TRIM25-induced K48-linked ubiquitination of MAVS. Taken together, our findings reveal an essential role of CypA in boosting RIG-I-mediated antiviral immune responses by controlling the ubiquitination of RIG-I and MAVS.

scholarly journals N6-methyladenosine RNA modification suppresses antiviral innate sensing pathways via reshaping double-stranded RNA

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Weinan Qiu ◽  
Qingyang Zhang ◽  
Rui Zhang ◽  
Yangxu Lu ◽  
Xin Wang ◽  
...  
Keyword(s):  
Rna Virus ◽  
Negative Regulator ◽  
Rna Modification ◽  
Type I ◽  
Viral Immunity ◽  
Potential Therapeutic Target ◽  
Viral Dsrna ◽  
Double Stranded Rna ◽  
Genetic Ablation ◽  
Vesicular Stomatitis

AbstractDouble-stranded RNA (dsRNA) is a virus-encoded signature capable of triggering intracellular Rig-like receptors (RLR) to activate antiviral signaling, but whether intercellular dsRNA structural reshaping mediated by the N6-methyladenosine (m6A) modification modulates this process remains largely unknown. Here, we show that, in response to infection by the RNA virus Vesicular Stomatitis Virus (VSV), the m6A methyltransferase METTL3 translocates into the cytoplasm to increase m6A modification on virus-derived transcripts and decrease viral dsRNA formation, thereby reducing virus-sensing efficacy by RLRs such as RIG-I and MDA5 and dampening antiviral immune signaling. Meanwhile, the genetic ablation of METTL3 in monocyte or hepatocyte causes enhanced type I IFN expression and accelerates VSV clearance. Our findings thus implicate METTL3-mediated m6A RNA modification on viral RNAs as a negative regulator for innate sensing pathways of dsRNA, and also hint METTL3 as a potential therapeutic target for the modulation of anti-viral immunity.

scholarly journals Novel Mode of ISG15-Mediated Protection against Influenza A Virus and Sendai Virus in Mice

2014 ◽  
Vol 89 (1) ◽  
pp. 337-349 ◽  
Author(s):  
David J. Morales ◽  
Kristen Monte ◽  
Lulu Sun ◽  
Jessica J. Struckhoff ◽  
Eugene Agapov ◽  
...  
Keyword(s):  
Tissue Culture ◽  
Virus Infection ◽  
Influenza A Virus ◽  
Virus Replication ◽  
Influenza A ◽  
Type I Interferon ◽  
Sendai Virus ◽  
Type I ◽  
Induced Genes

ABSTRACTISG15 is a diubiquitin-like modifier and one of the most rapidly induced genes upon type I interferon stimulation. Hundreds of host proteins and a number of viral proteins have been shown to be ISGylated, and understanding how these modifications affect the interferon response and virus replication has been of considerable interest. ISG15−/−mice exhibit increased susceptibility to viral infection, and in the case of influenza B virus and vaccinia virus, ISG15 conjugation has been shown to restrict virus replicationin vivo. A number of studies have also found that ISG15 is capable of antagonizing replication of some viruses in tissue culture. However, recent findings have demonstrated that ISG15 can protect mice from Chikungunya virus infection without affecting the virus burden. In order to better understand the function of ISG15in vivo, we characterized the pathogenesis of influenza A virus and Sendai virus in ISG15−/−mice. We found that ISG15 protects mice from virus induced lethality by a conjugation-dependent mechanism in both of these models. However, surprisingly, we found that ISG15 had minimal effect on virus replication and did not have an obvious role in the modulation of the acute immune response to infection. Instead, we observed an increase in the number of diseased small airways in mice lacking ISG15. This ability of ISG15 to protect mice in a conjugation-dependent, but nonantiviral, manner from respiratory virus infection represents a previously undescribed role for ISG15 and demonstrates the importance of further characterization of ISG15in vivo.IMPORTANCEIt has previously been demonstrated that ISG15−/−mice are more susceptible to a number of viral infections. Since ISG15 is one of the most strongly induced genes after type I interferon stimulation, analysis of ISG15 function has largely focused on its role as an antiviral molecule during acute infection. Although a number of studies have shown that ISG15 does have a small effect on virus replication in tissue culture, few studies have confirmed this mechanism of protectionin vivo. In these studies we have found that while ISG15−/−mice are more susceptible to influenza A virus and Sendai virus infections, ISGylation does not appear to mediate this protection through the direct inhibition of virus replication or the modulation of the acute immune response. Thus, in addition to showing a novel mode of ISG15 mediated protection from virus infection, this study demonstrates the importance of studying the role of ISG15in vivo.

scholarly journals Viral RNA at Two Stages of Reovirus Infection Is Required for the Induction of Necroptosis

2017 ◽  
Vol 91 (6) ◽  
Author(s):  
Angela K. Berger ◽  
Bradley E. Hiller ◽  
Deepti Thete ◽  
Anthony J. Snyder ◽  
Encarnacion Perez ◽  
...  
Keyword(s):  
Cell Death ◽  
Immune System ◽  
Virus Infection ◽  
De Novo ◽  
Rna Virus ◽  
Viral Rna ◽  
Host Cells ◽  
Type I ◽  
Tissue Destruction ◽  
Reovirus Infection

ABSTRACT Necroptosis, a regulated form of necrotic cell death, requires the activation of the RIP3 kinase. Here, we identify that infection of host cells with reovirus can result in necroptosis. We find that necroptosis requires sensing of the genomic RNA within incoming virus particles via cytoplasmic RNA sensors to produce type I interferon (IFN). While these events that occur prior to the de novo synthesis of viral RNA are required for the induction of necroptosis, they are not sufficient. The induction of necroptosis also requires late stages of reovirus infection. Specifically, efficient synthesis of double-stranded RNA (dsRNA) within infected cells is required for necroptosis. These data indicate that viral RNA interfaces with host components at two different stages of infection to induce necroptosis. This work provides new molecular details about events in the viral replication cycle that contribute to the induction of necroptosis following infection with an RNA virus. IMPORTANCE An appreciation of how cell death pathways are regulated following viral infection may reveal strategies to limit tissue destruction and prevent the onset of disease. Cell death following virus infection can occur by apoptosis or a regulated form of necrosis known as necroptosis. Apoptotic cells are typically disposed of without activating the immune system. In contrast, necroptotic cells alert the immune system, resulting in inflammation and tissue damage. While apoptosis following virus infection has been extensively investigated, how necroptosis is unleashed following virus infection is understood for only a small group of viruses. Here, using mammalian reovirus, we highlight the molecular mechanism by which infection with a dsRNA virus results in necroptosis.

scholarly journals Apoptosis in the Mouse Central Nervous System in Response to Infection with Mouse-Neurovirulent Dengue Viruses

1998 ◽  
Vol 72 (1) ◽  
pp. 823-829 ◽  
Author(s):  
Philippe Desprès ◽  
Marie-Pascale Frenkiel ◽  
Pierre-Emmanuel Ceccaldi ◽  
Claudia Duarte Dos Santos ◽  
Vincent Deubel
Keyword(s):  
Central Nervous System ◽  
Cell Death ◽  
Nervous System ◽  
Virus Infection ◽  
Virus Replication ◽  
Parental Strain ◽  
Apoptotic Cell ◽  
Neuronal Cell ◽  
Induced Apoptosis

ABSTRACT Apoptosis has been suggested as a mechanism by which dengue (DEN) virus infection may cause neuronal cell death (P. Desprès, M. Flamand, P.-E. Ceccaldi, and V. Deubel, J. Virol. 70:4090–4096, 1996). In this study, we investigated whether apoptotic cell death occurred in the central nervous system (CNS) of neonatal mice inoculated intracerebrally with DEN virus. We showed that serial passage of a wild-type human isolate of DEN virus in mouse brains selected highly neurovirulent variants which replicated more efficiently in the CNS. Infection of newborn mice with these neurovirulent variants produced fatal encephalitis within 10 days after inoculation. Virus-induced cell death and oligonucleosomal DNA fragmentation were observed in mouse brain tissue by day 9. Infected mouse brain tissue was assayed for apoptosis by in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and for virus replication by immunostaining of viral antigens and in situ hybridization. Apoptotic cell death and DEN virus replication were restricted to the neurons of the cortical and hippocampal regions. Thus, DEN virus-induced apoptosis in the CNS was a direct result of virus infection. In the murine neuronal cell line Neuro 2a, neuroadapted DEN virus variants showed infection patterns similar to those of the parental strain. However, DEN virus-induced apoptosis in these cells was more pronounced after infection with the neurovirulent variants than after infection with the parental strain.

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