Adenovirus vectors activate Vδ2 + γδT cells in a type I interferon‐, TNF‐, and IL‐18‐dependent manner

Mutations of Ubiquilin 2 (UBQLN2) or TANK-binding kinase 1 (TBK1) are associated with amyotrophic lateral sclerosis and frontotemporal degeneration (ALS/FTD). However, the mechanisms whereby UBQLN2 or TBK1 mutations lead to ALS and FTD remain unclear. Here, we explored the effect of UBQLN2 on TBK1 in HEK-293T cells or in CRISPR–Cas9-mediated IRF3 and IRF7 knockout (KO) cells. We found an interaction between TBK1 and UBQLN2, which was affected by ALS/FTD-linked mutations in TBK1 or UBQLN2. Co-expression of UBQLN2 with TBK1 elevated the protein level of TBK1 as well as the phosphorylation of TBK1 and IRF3 in a UBQLN2 dose-dependent manner, and this phosphorylation was reduced by mutant UBQLN2. In addition, the cellular production of IFN1 and related pro-inflammatory cytokines was substantially elevated when UBQLN2 and TBK1 were co-expressed, which was also decreased by mutant UBQLN2. Functional assay revealed that mutant UBQLN2 significantly reduced the binding affinity of TBK1 for its partners, including IRF3, (SQSTM1)/p62 and optineurin (OPTN). Moreover, complete loss of IRF3 abolished the induction of IFN1 and related pro-inflammatory cytokines enhanced by UBQLN2 in HEK-293T cells, whereas no significant change in IRF7 knockout cells was observed. Thus, our findings suggest that UBQLN2 promotes IRF3 phosphorylation via TBK1, leading to enhanced IFN1 induction, and also imply that the dysregulated TBK1-IRF3 pathway may play a role in UBQLN2-related neurodegeneration.

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Rabies Virus Infection Induces Type I Interferon Production in an IPS-1 Dependent Manner While Dendritic Cell Activation Relies on IFNAR Signaling

PLoS Pathogens ◽

10.1371/journal.ppat.1001016 ◽

2010 ◽

Vol 6 (7) ◽

pp. e1001016 ◽

Cited By ~ 61

Author(s):

Elizabeth J. Faul ◽

Celestine N. Wanjalla ◽

Mehul S. Suthar ◽

Michael Gale ◽

Christoph Wirblich ◽

...

Keyword(s):

Dendritic Cell ◽

Virus Infection ◽

Rabies Virus ◽

Cell Activation ◽

Type I Interferon ◽

Type I ◽

Dependent Manner ◽

Interferon Production ◽

Dendritic Cell Activation ◽

Rabies Virus Infection

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PP2A Facilitates Porcine Reproductive and Respiratory Syndrome Virus Replication by Deactivating irf3 and Limiting Type I Interferon Production

Viruses ◽

10.3390/v11100948 ◽

2019 ◽

Vol 11 (10) ◽

pp. 948 ◽

Cited By ~ 1

Author(s):

Jiayu Xu ◽

Lu Zhang ◽

Yunfei Xu ◽

He Zhang ◽

Junxin Gao ◽

...

Keyword(s):

Virus Infection ◽

Therapeutic Target ◽

Type I Interferon ◽

Negative Regulator ◽

Host Cells ◽

Respiratory Syndrome Virus ◽

Target Cells ◽

Type I ◽

Dependent Manner ◽

Pp2a Activity

Protein phosphatase 2A (PP2A), a major serine/threonine phosphatase in mammalian cells, is known to regulate the kinase-driven intracellular signaling pathways. Emerging evidences have shown that the PP2A phosphatase functions as a bona-fide therapeutic target for anticancer therapy, but it is unclear whether PP2A affects a porcine reproductive and respiratory syndrome virus infection. In the present study, we demonstrated for the first time that inhibition of PP2A activity by either inhibitor or small interfering RNA duplexes in target cells significantly reduced their susceptibility to porcine reproductive and respiratory syndrome virus (PRRSV) infection. Further analysis revealed that inhibition of PP2A function resulted in augmented production of type I interferon (IFN). The mechanism is that inhibition of PP2A activity enhances the levels of phosphorylated interferon regulatory factor 3, which activates the transcription of IFN-stimulated genes. Moreover, inhibition of PP2A activity mainly blocked PRRSV replication in the early stage of viral life cycle, after virus entry but before virus release. Using type I IFN receptor 2 specific siRNA in combination with PP2A inhibitor, we confirmed that the effect of PP2A on viral replication within target cells was an interferon-dependent manner. Taken together, these findings demonstrate that PP2A serves as a negative regulator of host cells antiviral responses and provides a novel therapeutic target for virus infection.

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SARS-CoV-2 nsp12 attenuates type I interferon production by inhibiting IRF3 nuclear translocation

Cellular and Molecular Immunology ◽

10.1038/s41423-020-00619-y ◽

2021 ◽

Author(s):

Wenjing Wang ◽

Zhuo Zhou ◽

Xia Xiao ◽

Zhongqin Tian ◽

Xiaojing Dong ◽

...

Keyword(s):

Nuclear Translocation ◽

Type I Interferon ◽

Sendai Virus ◽

Polymerase Activity ◽

Poly I:C ◽

Type I ◽

Dependent Manner ◽

Promoter Activation ◽

Global Pandemic ◽

Antiviral Innate Immunity

AbstractSARS-CoV-2 is the pathogenic agent of COVID-19, which has evolved into a global pandemic. Compared with some other respiratory RNA viruses, SARS-CoV-2 is a poor inducer of type I interferon (IFN). Here, we report that SARS-CoV-2 nsp12, the viral RNA-dependent RNA polymerase (RdRp), suppresses host antiviral responses. SARS-CoV-2 nsp12 attenuated Sendai virus (SeV)- or poly(I:C)-induced IFN-β promoter activation in a dose-dependent manner. It also inhibited IFN promoter activation triggered by RIG-I, MDA5, MAVS, and IRF3 overexpression. Nsp12 did not impair IRF3 phosphorylation but suppressed the nuclear translocation of IRF3. Mutational analyses suggested that this suppression was not dependent on the polymerase activity of nsp12. Given these findings, our study reveals that SARS-CoV-2 RdRp can antagonize host antiviral innate immunity and thus provides insights into viral pathogenesis.

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Tumor PD-L1 selectively suppresses type I interferon in myeloid cells to suppress CTL recruitment to promote lung metastasis

10.1101/2021.06.18.449028 ◽

2021 ◽

Author(s):

John D Klement ◽

Priscilla S Redd ◽

Chunwan Lu ◽

Alyssa D Merting ◽

Dakota B Poschel ◽

...

Keyword(s):

Tumor Cells ◽

Lung Metastasis ◽

Immune Suppression ◽

Type I Interferon ◽

Lung Metastases ◽

Myeloid Cells ◽

Type I ◽

Intermediate Cell ◽

Dependent Manner ◽

Human Patient

The mechanism underlying tumor cell PD-L1 (tPD-L1) induction of immune suppression through T cell PD-1 is well-known, but the mechanism underlying tPD-L1 induction of immune suppression via an intermediate cell is incompletely understood. We report here that tPD-L1 does not suppress cytotoxic T lymphocyte (CTL) activation and lytic function when only tumor cells and CTLs are present. Strikingly, knocking out PD-L1 in tumor cells has no effect on primary tumor growth, but significantly decreases lung metastasis in a CTL-dependent manner. Depletion of myeloid cells impaired tPD-L1 promotion of lung metastasis. Single-cell RNA sequencing revealed that tPD-L1 engages myeloid PD-1 (mPD-1) to antagonize type I interferon (IFN-I) and STAT1 signaling to repress Cxcl9 and Cxcl10 expression to impair CTL recruitment to lung metastases. Human patient response to PD-1 blockade immunotherapy correlates with IFN-I response in myeloid cells. Our data determines that the tPD-L1/mPD-1/IFN-I/STAT1/Cxcl9/10 axis controls CTL tumor infiltration in lung metastasis.

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Bud13 Promotes a Type I Interferon Response by Countering Intron Retention in Irf7

10.1101/443820 ◽

2018 ◽

Author(s):

Luke S. Frankiw ◽

Devdoot Majumdar ◽

Christian Burns ◽

Annie Moradian ◽

Michael J. Sweredoski ◽

...

Keyword(s):

Rna Binding ◽

Type I Interferon ◽

Intron Retention ◽

Global Analysis ◽

Interferon Response ◽

Type I ◽

Dependent Manner ◽

Protein Levels ◽

Expression Of Genes ◽

Gene Expression Control

SUMMARYIntron retention (IR) has emerged as an important mechanism of gene expression control. Despite this, the factors that control IR events remain poorly understood. We observed consistent IR in one intron of the Irf7 gene and identified Bud13 as an RNA-binding protein that acts at this intron to increase the amount of successful splicing. Deficiency in Bud13 led to increased IR, decreased mature Irf7 transcript and protein levels, and consequently to a dampened type I interferon response. This impairment of Irf7 production in Bud13-deficient cells compromised their ability to withstand VSV infection. Global analysis of Bud13 knockdown and BUD13 cross-linking to RNA revealed a subset of introns that share many characteristics with the one found in Irf7 and are spliced in a Bud13-dependent manner. Deficiency of Bud13 led to decreased mature transcript from genes containing such introns. Thus, by acting as an antagonist to IR, Bud13 facilitates the expression of genes at which IR occurs.

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Influenza Virus Protein PB1-F2 Inhibits the Induction of Type I Interferon by Binding to MAVS and Decreasing Mitochondrial Membrane Potential

Journal of Virology ◽

10.1128/jvi.01122-12 ◽

2012 ◽

Vol 86 (16) ◽

pp. 8359-8366 ◽

Cited By ~ 117

Author(s):

Zsuzsanna T. Varga ◽

Alesha Grant ◽

Balaji Manicassamy ◽

Peter Palese

Keyword(s):

Influenza Virus ◽

Membrane Potential ◽

Molecular Mechanism ◽

Mitochondrial Membrane Potential ◽

Mitochondrial Membrane ◽

Transmembrane Domain ◽

Type I Interferon ◽

Adaptor Protein ◽

Type I ◽

Dependent Manner

PB1-F2 is a small, 87- to 90-amino-acid-long protein encoded by the +1 alternate open reading frame of the PB1 gene of most influenza A virus strains. It has been shown to contribute to viral pathogenicity in a host- and strain-dependent manner, and we have previously discovered that a serine at position 66 (66S) in the PB1-F2 protein increases virulence of the 1918 and H5N1 pandemic viruses. Recently, we have shown that PB1-F2 inhibits the induction of type I interferon (IFN) at the level of the MAVS adaptor protein. However, the molecular mechanism for the IFN antagonist function of PB1-F2 has remained unclear. In the present study, we demonstrated that the C-terminal portion of the PB1-F2 protein binds to MAVS in a region that contains the transmembrane domain. Strikingly, PB1-F2 66S was observed to bind to MAVS more efficiently than PB1-F2 66N. We also tested the effect of PB1-F2 on the IFN antagonist functions of the polymerase proteins PB1, PB2, and PA and observed enhanced IFN inhibition by the PB1 and PB2 proteins in combination with PB1-F2 but not by the PA protein. Using a flow cytometry-based assay, we demonstrate that the PB1-F2 protein inhibits MAVS-mediated IFN synthesis by decreasing the mitochondrial membrane potential (MMP). Interestingly, PB1-F2 66S affected the MMP more efficiently than wild-type PB1-F2. In summary, the results of our study identify the molecular mechanism by which the influenza virus PB1-F2 N66S protein increases virulence.

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Infectious Bronchitis Coronavirus Inhibits STAT1 Signaling and Requires Accessory Proteins for Resistance to Type I Interferon Activity

Journal of Virology ◽

10.1128/jvi.01057-15 ◽

2015 ◽

Vol 89 (23) ◽

pp. 12047-12057 ◽

Cited By ~ 23

Author(s):

Joeri Kint ◽

Annemiek Dickhout ◽

Jasmin Kutter ◽

Helena J. Maier ◽

Paul Britton ◽

...

Keyword(s):

Infectious Bronchitis Virus ◽

Type I Interferon ◽

Accessory Protein ◽

Type I ◽

Avian Host ◽

Accessory Proteins ◽

Dependent Manner ◽

Infectious Bronchitis ◽

Multiple Strategies ◽

Ifn Treatment

ABSTRACTThe innate immune response is the first line of defense against viruses, and type I interferon (IFN) is a critical component of this response. Similar to other viruses, the gammacoronavirus infectious bronchitis virus (IBV) has evolved under evolutionary pressure to evade and counteract the IFN response to enable its survival. Previously, we reported that IBV induces a delayed activation of the IFN response. In the present work, we describe the resistance of IBV to IFN and the potential role of accessory proteins herein. We show that IBV is fairly resistant to the antiviral state induced by IFN and identify that viral accessory protein 3a is involved in resistance to IFN, as its absence renders IBV less resistant to IFN treatment. In addition to this, we found that independently of its accessory proteins, IBV inhibits IFN-mediated phosphorylation and translocation of STAT1. In summary, we show that IBV uses multiple strategies to counteract the IFN response.IMPORTANCEIn the present study, we show that infectious bronchitis virus (IBV) is resistant to IFN treatment and identify a role for accessory protein 3a in the resistance against the type I IFN response. We also demonstrate that, in a time-dependent manner, IBV effectively interferes with IFN signaling and that its accessory proteins are dispensable for this activity. This study demonstrates that the gammacoronavirus IBV, similar to its mammalian counterparts, has evolved multiple strategies to efficiently counteract the IFN response of its avian host, and it identifies accessory protein 3a as multifaceted antagonist of the avian IFN system.

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