scholarly journals Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Membrane (M) and Spike (S) Proteins Antagonize Host Type I Interferon Response

2021 ◽  
Vol 11 ◽  
Author(s):  
Qi Zhang ◽  
Zhiqiang Chen ◽  
Chenxiao Huang ◽  
Jiuyuan Sun ◽  
Minfei Xue ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Type I Interferon ◽  
Typical Feature ◽  
Janus Kinase ◽  
Interferon Response ◽  
Type I ◽  
Downstream Signaling ◽  
Janus Kinase 1

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide and has infected more than 250 million people. A typical feature of COVID-19 is the lack of type I interferon (IFN-I)-mediated antiviral immunity in patients. However, the detailed molecular mechanisms by which SARS-CoV-2 evades the IFN-I-mediated antiviral response remain elusive. Here, we performed a comprehensive screening and identified a set of SARS-CoV-2 proteins that antagonize the IFN-I response. Subsequently, we characterized the mechanisms of two viral proteins antagonize IFN-I production and downstream signaling. SARS-CoV-2 membrane protein binds to importin karyopherin subunit alpha-6 (KPNA6) to inhibit interferon regulatory factor 3(IRF3) nuclear translocation. Further, the spike protein interacts with signal transducer and activator of transcription 1 (STAT1) to block its association with Janus kinase 1 (JAK1). This study increases our understanding of SARS-CoV-2 pathogenesis and suggests novel therapeutic targets for the treatment of COVID-19.

scholarly journals Differential Inhibition of Type I Interferon Induction by Arenavirus Nucleoproteins

2007 ◽  
Vol 81 (22) ◽  
pp. 12696-12703 ◽  
Author(s):  
Luis Martínez-Sobrido ◽  
Panagiotis Giannakas ◽  
Beatrice Cubitt ◽  
Adolfo García-Sastre ◽  
Juan Carlos de la Torre
Keyword(s):  
New World ◽  
Nuclear Translocation ◽  
Type I Interferon ◽  
Lymphocytic Choriomeningitis ◽  
Interferon Response ◽  
Type I ◽  
Regulatory Factor ◽  
Interferon Induction ◽  
Tacaribe Virus ◽  
Infected Cells

ABSTRACT We have documented that the nucleoprotein (NP) of the prototypic arenavirus lymphocytic choriomeningitis virus is an antagonist of the type I interferon response. In this study we tested the ability of NPs encoded by representative arenavirus species from both Old World and New World antigenic groups to inhibit production of interferon. We found that, with the exception of Tacaribe virus (TCRV), all NPs tested inhibited activation of beta interferon and interferon regulatory factor 3 (IRF-3)-dependent promoters, as well as the nuclear translocation of IRF-3. Consistent with this observation, TCRV-infected cells also failed to inhibit interferon production.

scholarly journals Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) membrane (M) protein inhibits type I and III interferon production by targeting RIG-I/MDA-5 signaling

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Yi Zheng ◽  
Meng-Wei Zhuang ◽  
Lulu Han ◽  
Jing Zhang ◽  
Mei-Ling Nan ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Nuclear Translocation ◽  
Ectopic Expression ◽  
Antiviral Immunity ◽  
Typical Feature ◽  
M Protein ◽  
Poly I:C ◽  
Type I ◽  
Vesicular Stomatitis ◽  
Insight Into

AbstractCoronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has quickly spread worldwide and has affected more than 10 million individuals. A typical feature of COVID-19 is the suppression of type I and III interferon (IFN)-mediated antiviral immunity. However, the molecular mechanism by which SARS-CoV-2 evades antiviral immunity remains elusive. Here, we reported that the SARS-CoV-2 membrane (M) protein inhibits the production of type I and III IFNs induced by the cytosolic dsRNA-sensing pathway mediated by RIG-I/MDA-5–MAVS signaling. In addition, the SARS-CoV-2 M protein suppresses type I and III IFN induction stimulated by SeV infection or poly (I:C) transfection. Mechanistically, the SARS-CoV-2 M protein interacts with RIG-I, MAVS, and TBK1, thus preventing the formation of the multiprotein complex containing RIG-I, MAVS, TRAF3, and TBK1 and subsequently impeding the phosphorylation, nuclear translocation, and activation of IRF3. Consequently, ectopic expression of the SARS-CoV-2 M protein facilitates the replication of vesicular stomatitis virus. Taken together, these results indicate that the SARS-CoV-2 M protein antagonizes type I and III IFN production by targeting RIG-I/MDA-5 signaling, which subsequently attenuates antiviral immunity and enhances viral replication. This study provides insight into the interpretation of SARS-CoV-2-induced antiviral immune suppression and illuminates the pathogenic mechanism of COVID-19.

scholarly journals SARS-CoV-2-Encoded MiRNAs Inhibit Host Type I Interferon Pathway and Mediate Allelic Differential Expression of Susceptible Gene

2021 ◽  
Vol 12 ◽  
Author(s):  
Youwei Zhu ◽  
Zhaoyang Zhang ◽  
Jia Song ◽  
Weizhou Qian ◽  
Xiangqian Gu ◽  
...  
Keyword(s):  
Differential Expression ◽  
Molecular Mechanisms ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Health Crisis ◽  
Host Interactions ◽  
Interferon Pathway ◽  
Host Innate Immune Response ◽  
Susceptible Gene

Infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the rapid spread of coronavirus disease 2019 (COVID-19), has generated a public health crisis worldwide. The molecular mechanisms of SARS-CoV-2 infection and virus–host interactions are still unclear. In this study, we identified four unique microRNA-like small RNAs encoded by SARS-CoV-2. SCV2-miR-ORF1ab-1-3p and SCV2-miR-ORF1ab-2-5p play an important role in evasion of type I interferon response through targeting several genes in type I interferon signaling pathway. Particularly worth mentioning is that highly expressed SCV2-miR-ORF1ab-2-5p inhibits some key genes in the host innate immune response, such as IRF7, IRF9, STAT2, OAS1, and OAS2. SCV2-miR-ORF1ab-2-5p has also been found to mediate allelic differential expression of COVID-19-susceptible gene OAS1. In conclusion, these results suggest that SARS-CoV-2 uses its miRNAs to evade the type I interferon response and links the functional viral sequence to the susceptible genetic background of the host.

scholarly journals ALG2 regulates type I interferon responses by inhibiting STING trafficking

2021 ◽  
Author(s):  
Wangsheng Ji ◽  
Lianfei Zhang ◽  
Xiaoyu Xu ◽  
Xinqi Liu
Keyword(s):  
Immune Responses ◽  
Type I Interferon ◽  
Innate Immune ◽  
Type I Interferons ◽  
Interferon Response ◽  
Type I ◽  
Innate Immune Responses ◽  
Downstream Signaling ◽  
Interferon Responses ◽  
Hsv 1

Stimulator of IFN genes (STING), an endoplasmic reticulum (ER) signaling adaptor, is essential for the type I interferon response to cytosolic dsDNA. The translocation from the ER to perinuclear vesicles following binding cGAMP is a critical step for STING to activate downstream signaling molecules, which lead to the production of interferon and pro-inflammatory cytokines. Here we found that apoptosis-linked gene 2 (ALG2) suppressed STING signaling induced by either HSV-1 infection or cGAMP presence. Knockout of ALG2 markedly facilitated the expression of type I interferons upon cGAMP treatment or HSV-1 infection in THP-1 monocytes. Mechanistically, ALG2 associated with the C-terminal tail (CTT) of STING and inhibited its trafficking from ER to perinuclear region. Furthermore, the ability of ALG2 to coordinate calcium was crucial for its regulation of STING trafficking and DNA-induced innate immune responses. This work suggests that ALG2 is involved in DNA-induced innate immune responses by regulating STING trafficking.

scholarly journals Porcine Epidemic Diarrhea Virus Infection Inhibits Interferon Signaling by Targeted Degradation of STAT1

2016 ◽  
Vol 90 (18) ◽  
pp. 8281-8292 ◽  
Author(s):  
Longjun Guo ◽  
Xiaolei Luo ◽  
Ren Li ◽  
Yunfei Xu ◽  
Jian Zhang ◽  
...  
Keyword(s):  
Virus Infection ◽  
Porcine Epidemic Diarrhea Virus ◽  
Molecular Mechanisms ◽  
Type I Interferon ◽  
Infection Type ◽  
Interferon Response ◽  
Type I ◽  
Dependent Manner ◽  
Diarrhea Virus ◽  
Porcine Epidemic Diarrhea

ABSTRACTPorcine epidemic diarrhea virus (PEDV) is a worldwide-distributed alphacoronavirus, but the pathogenesis of PEDV infection is not fully characterized. During virus infection, type I interferon (IFN) is a key mediator of innate antiviral responses. Most coronaviruses develop some strategy for at least partially circumventing the IFN response by limiting the production of IFN and by delaying the activation of the IFN response. However, the molecular mechanisms by which PEDV antagonizes the antiviral effects of interferon have not been fully characterized. Especially, how PEDV impacts IFN signaling components has yet to be elucidated. In this study, we observed that PEDV was relatively resistant to treatment with type I IFN. Western blot analysis showed that STAT1 expression was markedly reduced in PEDV-infected cells and that this reduction was not due to inhibition of STAT1 transcription. STAT1 downregulation was blocked by a proteasome inhibitor but not by an autophagy inhibitor, strongly implicating the ubiquitin-proteasome targeting degradation system. Since PEDV infection-induced STAT1 degradation was evident in cells pretreated with the general tyrosine kinase inhibitor, we conclude that STAT1 degradation is independent of the IFN signaling pathway. Furthermore, we report that PEDV-induced STAT1 degradation inhibits IFN-α signal transduction pathways. Pharmacological inhibition of STAT1 degradation rescued the ability of the host to suppress virus replication. Collectively, these data show that PEDV is capable of subverting the type I interferon response by inducing STAT1 degradation.IMPORTANCEIn this study, we show that PEDV is resistant to the antiviral effect of IFN. The molecular mechanism is the degradation of STAT1 by PEDV infection in a proteasome-dependent manner. This PEDV infection-induced STAT1 degradation contributes to PEDV replication. Our findings reveal a new mechanism evolved by PEDV to circumvent the host antiviral response.

scholarly journals La Piedad Michoacán Mexico Virus V protein antagonizes type I interferon response by binding STAT2 protein and preventing STATs nuclear translocation

2016 ◽  
Vol 213 ◽  
pp. 11-22 ◽  
Author(s):  
Giuseppe Pisanelli ◽  
Maudry Laurent-Rolle ◽  
Balaji Manicassamy ◽  
Alan Belicha-Villanueva ◽  
Juliet Morrison ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
V Protein

Viral Invasion and Type I Interferon Response Characterize the Immunophenotypes during COVID-19 Infection

2020 ◽  
Author(s):  
Lai Wei ◽  
Siqi Ming ◽  
Bin Zou ◽  
Yongjian Wu ◽  
Zhongsi Hong ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Interferon Response ◽  
Type I

scholarly journals PRV UL13 inhibits cGAS–STING-mediated IFN-β production by phosphorylating IRF3

2020 ◽  
Vol 51 (1) ◽  
Author(s):  
Zongyi Bo ◽  
Yurun Miao ◽  
Rui Xi ◽  
Qiuping Zhong ◽  
Chenyi Bao ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Pseudorabies Virus ◽  
Nuclear Translocation ◽  
Economic Loss ◽  
Inhibitory Effect ◽  
Poly I:C ◽  
Interferon Response ◽  
Type I ◽  
Creb Binding Protein ◽  
Swine Industry

Abstract Cyclic GMP-AMP (cGAMP) synthase (cGAS) is an intracellular sensor of cytoplasmic viral DNA created during virus infection, which subsequently activates the stimulator of interferon gene (STING)-dependent type I interferon response to eliminate pathogens. In contrast, viruses have developed different strategies to modulate this signalling pathway. Pseudorabies virus (PRV), an alphaherpesvirus, is the causative agent of Aujeszky’s disease (AD), a notable disease that causes substantial economic loss to the swine industry globally. Previous reports have shown that PRV infection induces cGAS-dependent IFN-β production, conversely hydrolysing cGAMP, a second messenger synthesized by cGAS, and attenuates PRV-induced IRF3 activation and IFN-β secretion. However, it is not clear whether PRV open reading frames (ORFs) modulate the cGAS–STING-IRF3 pathway. Here, 50 PRV ORFs were screened, showing that PRV UL13 serine/threonine kinase blocks the cGAS–STING-IRF3-, poly(I:C)- or VSV-mediated transcriptional activation of the IFN-β gene. Importantly, it was discovered that UL13 phosphorylates IRF3, and its kinase activity is indispensable for such an inhibitory effect. Moreover, UL13 does not affect IRF3 dimerization, nuclear translocation or association with CREB-binding protein (CBP) but attenuates the binding of IRF3 to the IRF3-responsive promoter. Consistent with this, it was discovered that UL13 inhibits the expression of multiple interferon-stimulated genes (ISGs) induced by cGAS–STING or poly(I:C). Finally, it was determined that PRV infection can activate IRF3 by recruiting it to the nucleus, and PRVΔUL13 mutants enhance the transactivation level of the IFN-β gene. Taken together, the data from the present study demonstrated that PRV UL13 inhibits cGAS–STING-mediated IFN-β production by phosphorylating IRF3.

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