scholarly journals Enterovirus 2Apro Cleavage of the YTHDF m6A Readers Implicates YTHDF3 as a Mediator of Type I Interferon-Driven JAK/STAT Signaling

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Jonathan P. Kastan ◽  
Martine W. Tremblay ◽  
Michael C. Brown ◽  
Joseph D. Trimarco ◽  
Elena Y. Dobrikova ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Biological Significance ◽  
Cell Manipulation ◽  
Type I ◽  
Messenger Rnas ◽  
Viral Translation ◽  
Antiviral Immune Response ◽  
Stat Signaling ◽  
Infected Cells ◽  
In Cells

ABSTRACT Enteroviruses (EV) deploy two proteases that mediate viral polyprotein cleavage and host cell manipulation. Here, we report that EV 2A proteases cleave all three members of the YTHDF protein family, cytosolic N6-methyladenosine (m6A) “readers” that regulate target mRNA fate. YTHDF protein cleavage occurs very early during infection, before viral translation is detected or cytopathogenic effects are observed. Preemptive YTHDF protein depletion enhanced viral translation and replication but only in cells with restrained viral translation, signs of inefficient 2A protease activity, and protective innate host immune responses. This effect corresponded with repression of interferon (IFN)-stimulated gene (ISG) induction, while type I/III IFN production was not significantly altered. Moreover, YTHDF3 depletion impaired JAK/STAT signaling in cells treated with type I, but not type II, IFN. YTHDF3 depletion’s stimulatory effect on viral dynamics was dampened by JAK/STAT blockade and enhanced by type I IFN pretreatment of cells. We propose that EV 2A proteases cleave YTHDF proteins to antagonize ISG induction in infected cells. IMPORTANCE It is believed that ∼7,000 messenger RNAs (mRNAs) are subject to N6-methyladenosine modification. The biological significance of this remains mysterious. The YTHDF m6A readers are three related proteins with high affinity for m6A-modified mRNA, yet their biological functions remain obscure. We discovered that polio/enteroviruses elicit very early proteolysis of YTHDF1 to 3 in infected cells. Our research demonstrates that YTHDF3 acts as a positive regulator of antiviral JAK/STAT signaling in response to positive single-strand RNA virus infection, enabling type I interferon (IFN)-mediated gene regulatory programs to unfurl in infected cells. Our observation of viral degradation of the YTHDF proteins demonstrates that they are key response modifiers in the innate antiviral immune response.

scholarly journals Inhibition of Interferon Signaling by Rabies Virus Phosphoprotein P: Activation-Dependent Binding of STAT1 and STAT2

2006 ◽  
Vol 80 (6) ◽  
pp. 2675-2683 ◽  
Author(s):  
Krzysztof Brzózka ◽  
Stefan Finke ◽  
Karl-Klaus Conzelmann
Keyword(s):  
Rabies Virus ◽  
Transcriptional Activation ◽  
Type I ◽  
Interferon Signaling ◽  
Cell Extracts ◽  
Independent Functions ◽  
Stat Signaling ◽  
Infected Cells ◽  
Ifn Γ ◽  
In Cells

ABSTRACT Rabies virus (RV) phosphoprotein P is an interferon (IFN) antagonist counteracting transcriptional activation of type I IFN (K. Brzózka, S. Finke, and K. K. Conzelmann, J. Virol 79:7673-7681, 2005). We here show that RV P in addition is responsible for preventing IFN-α/β- and IFN-γ-stimulated JAK-STAT signaling in RV-infected cells by the retention of activated STATs in the cytoplasm. Expression of IFN-stimulated response element- and gamma-activated sequence-controlled genes was severely impaired in cells infected with RV SAD L16 or in cells expressing RV P protein from transfected plasmids. In contrast, a recombinant RV expressing small amounts of P had lost the ability to interfere with JAK-STAT signaling. IFN-mediated tyrosine phosphorylation of STAT1 and STAT2 was not impaired in RV P-expressing cells; rather, a defect in STAT recycling was suggested by distinct accumulation of tyrosine-phosphorylated STATs in cell extracts. In the presence of P, activated STAT1 and STAT2 were unable to accumulate in the nucleus. Notably, STAT1 and STAT2 were coprecipitated with RV P only from extracts of cells previously stimulated with IFN-α or IFN-γ, whereas in nonstimulated cells no association of P with STATs was observed. This conditional, IFN activation-dependent binding of tyrosine-phosphorylated STATs by RV P is unique for a viral IFN antagonist. The 10 C-terminal residues of P are required for counteracting JAK-STAT signaling but not for inhibition of transcriptional activation of IFN-β, thus demonstrating two independent functions of RV P in counteracting the host's IFN response.

scholarly journals Human plasmacytoid dendritic cells mount a distinct antiviral response to virus-infected cells

2021 ◽  
Vol 6 (58) ◽  
pp. eabc7302
Author(s):  
Tae Jin Yun ◽  
Suzu Igarashi ◽  
Haoquan Zhao ◽  
Oriana A. Perez ◽  
Marcus R. Pereira ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Virus Detection ◽  
Plasmacytoid Dendritic Cells ◽  
Lung Epithelial Cells ◽  
Live Cells ◽  
Type I ◽  
Antiviral Immune Response ◽  
Lung Epithelial ◽  
Functional Consequences ◽  
Infected Cells

Plasmacytoid dendritic cells (pDCs) can rapidly produce interferons and other soluble factors in response to extracellular viruses or virus mimics such as CpG-containing DNA. pDCs can also recognize live cells infected with certain RNA viruses, but the relevance and functional consequences of such recognition remain unclear. We studied the response of primary DCs to the prototypical persistent DNA virus, human cytomegalovirus (CMV). Human pDCs produced high amounts of type I interferon (IFN-I) when incubated with live CMV-infected fibroblasts but not with free CMV; the response involved integrin-mediated adhesion, transfer of DNA-containing virions to pDCs, and the recognition of DNA through TLR9. Compared with transient polyfunctional responses to CpG or free influenza virus, pDC response to CMV-infected cells was long-lasting, dominated by the production of IFN-I and IFN-III, and lacked diversification into functionally distinct populations. Similarly, pDC activation by influenza-infected lung epithelial cells was highly efficient, prolonged, and dominated by interferon production. Prolonged pDC activation by CMV-infected cells facilitated the activation of natural killer cells critical for CMV control. Last, patients with CMV viremia harbored phenotypically activated pDCs and increased circulating IFN-I and IFN-III. Thus, recognition of live infected cells is a mechanism of virus detection by pDCs that elicits a unique antiviral immune response.

187 Glucocorticoid regulation of the type I interferon-JAK/STAT signaling pathway

Cytokine ◽  
2008 ◽  
Vol 43 (3) ◽  
pp. 283-284
Author(s):  
Jamie R. Flammer ◽  
Megan A. Kennedy ◽  
Yurii Chinenov ◽  
Lionel B. Ivashkiv ◽  
Inez Rogatsky
Keyword(s):  
Signaling Pathway ◽  
Type I Interferon ◽  
Type I ◽  
Stat Signaling

scholarly journals Attenuation of the type I interferon response in cells infected with human rhinovirus

Virology ◽  
2008 ◽  
Vol 374 (2) ◽  
pp. 399-410 ◽  
Author(s):  
Swathi Kotla ◽  
Tao Peng ◽  
Roger E. Bumgarner ◽  
Kurt E. Gustin
Keyword(s):  
Type I Interferon ◽  
Human Rhinovirus ◽  
Interferon Response ◽  
Type I ◽  
In Cells

scholarly journals A cytomegaloviral protein reveals a dual role for STAT2 in IFN-γ signaling and antiviral responses

2005 ◽  
Vol 201 (10) ◽  
pp. 1543-1553 ◽  
Author(s):  
Albert Zimmermann ◽  
Mirko Trilling ◽  
Markus Wagner ◽  
Manuel Wilborn ◽  
Ivan Bubic ◽  
...  
Keyword(s):  
Biological Significance ◽  
Receptor Expression ◽  
Type I ◽  
Antiviral Responses ◽  
Type I Ifns ◽  
New Strategy ◽  
Infected Cells ◽  
Ifn Γ

A mouse cytomegalovirus (MCMV) gene conferring interferon (IFN) resistance was identified. This gene, M27, encodes a 79-kD protein that selectively binds and down-regulates for signal transducer and activator of transcription (STAT)-2, but it has no effect on STAT1 activation and signaling. The absence of pM27 conferred MCMV susceptibility to type I IFNs (α/β), but it had a much more dramatic effect on type II IFNs (γ) in vitro and in vivo. A comparative analysis of M27+ and M27− MCMV revealed that the antiviral efficiency of IFN-γ was partially dependent on the synergistic action of type I IFNs that required STAT2. Moreover, STAT2 was directly activated by IFN-γ. This effect required IFN receptor expression and was independent of type I IFNs. IFN-γ induced increasing levels of tyrosine-phosphorylated STAT2 in M27− MCMV-infected cells that were essential for the antiviral potency of IFN-γ. pM27 represents a new strategy for simultaneous evasions from types I and II IFNs, and it documents an unknown biological significance for STAT2 in antiviral IFN-γ responses.

scholarly journals Efficient dengue virus (DENV) infection of human muscle satellite cells upregulates type I interferon response genes and differentially modulates MHC I expression on bystander and DENV-infected cells

2008 ◽  
Vol 89 (7) ◽  
pp. 1605-1615 ◽  
Author(s):  
Rajas V. Warke ◽  
Aniuska Becerra ◽  
Agatha Zawadzka ◽  
Diane J. Schmidt ◽  
Katherine J. Martin ◽  
...  
Keyword(s):  
Cell Surface ◽  
Satellite Cells ◽  
Culture Medium ◽  
Type I Interferon ◽  
Denv Infection ◽  
Human Muscle ◽  
Type I ◽  
Mhc I ◽  
Muscle Satellite Cells ◽  
Infected Cells

Dengue virus (DENV) is a mosquito-borne flavivirus that causes an acute febrile disease in humans, characterized by musculoskeletal pain, headache, rash and leukopenia. The cause of myalgia during DENV infection is still unknown. To determine whether DENV can infect primary muscle cells, human muscle satellite cells were exposed to DENV in vitro. The results demonstrated for the first time high-efficiency infection and replication of DENV in human primary muscle satellite cells. Changes in global gene expression were also examined in these cells following DENV infection using Affymetrix GeneChip analysis. The differentially regulated genes belonged to two main functional categories: cell growth and development, and antiviral type I interferon (IFN) response genes. Increased expression of the type I IFN response genes for tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), melanoma-derived antigen 5 (MDA-5), IFN-γ-inducible protein 10 (IP-10), galectin 3 soluble binding protein (LGals3BP) and IFN response factor 7 (IRF7) was confirmed by quantitative RT-PCR. Furthermore, higher levels of cell-surface-bound intracellular adhesion molecule-1 (ICAM-1) and soluble ICAM-1 in the cell-culture medium were detected following DENV infection. However, DENV infection impaired the ability of the infected cells in the culture medium to upregulate cell-surface expression of MHC I molecules, suggesting a possible mechanism of immune evasion by DENV. The findings of this study warrant further clinical research to identify whether muscle cells are targets for DENV infection during the acute stage of the disease in vivo.

scholarly journals Complement Potentiates Immune Sensing of HIV-1 and Early Type I Interferon Responses

mBio ◽  
2021 ◽  
Author(s):  
Wilfried Posch ◽  
Marta Bermejo-Jambrina ◽  
Marion Steger ◽  
Christina Witting ◽  
Gabriel Diem ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Therapeutic Interventions ◽  
Complement Receptor ◽  
Type I ◽  
Early Type ◽  
Antiviral Immune Response ◽  
Immune Sensing ◽  
Interferon Responses ◽  
Hiv 1 ◽  
Subsequent Opening

Importantly, our study highlights an unusual target on DCs—the α chain of complement receptor 4 (CR4) (CD11c)—for therapeutic interventions in HIV-1 treatment. Targeting CD11c on DCs mediated a potent antiviral immune response via clustering of CR4 and CCR5 and subsequent opening of an antiviral recognition pathway in DCs via MAVS.

Transcriptome analysis of senecavirus A-infected cells: Type I interferon is a critical anti-viral factor

2020 ◽  
Vol 147 ◽  
pp. 104432
Author(s):  
Jing Wang ◽  
Chunxiao Mou ◽  
Minmin Wang ◽  
Shuonan Pan ◽  
Zhenhai Chen
Keyword(s):  
Transcriptome Analysis ◽  
Type I Interferon ◽  
Type I ◽  
Viral Factor ◽  
Infected Cells

scholarly journals Epstein-Barr Virus (EBV) Tegument Protein BGLF2 Suppresses Type I Interferon Signaling To Promote EBV Reactivation

2020 ◽  
Vol 94 (11) ◽  
Author(s):  
XueQiao Liu ◽  
Tomohiko Sadaoka ◽  
Tammy Krogmann ◽  
Jeffrey I. Cohen
Keyword(s):  
Virus Infection ◽  
Type I Interferon ◽  
Tegument Protein ◽  
Type I ◽  
Type I Ifn ◽  
Virus Reactivation ◽  
Ebv Infection ◽  
Ebv Reactivation ◽  
Stat3 Phosphorylation ◽  
Infected Cells

ABSTRACT Interferon alpha (IFN-α) and IFN-β are type I IFNs that are induced by virus infection and are important in the host’s innate antiviral response. EBV infection activates multiple cell signaling pathways, resulting in the production of type I IFN which inhibits EBV infection and virus-induced B-cell transformation. We reported previously that EBV tegument protein BGLF2 activates p38 and enhances EBV reactivation. To further understand the role of BGLF2 in EBV infection, we used mass spectrometry to identify cellular proteins that interact with BGLF2. We found that BGLF2 binds to Tyk2 and confirmed this interaction by coimmunoprecipitation. BGLF2 blocked type I IFN-induced Tyk2, STAT1, and STAT3 phosphorylation and the expression of IFN-stimulated genes (ISGs) IRF1, IRF7, and MxA. In contrast, BGLF2 did not inhibit STAT1 phosphorylation induced by IFN-γ. Deletion of the carboxyl-terminal 66 amino acids of BGLF2 reduced the ability of the protein to repress type I IFN signaling. Treatment of gastric carcinoma and Raji cells with IFN-α blocked BZLF1 expression and EBV reactivation; however, expression of BGLF2 reduced the ability of IFN-α to inhibit BZLF1 expression and enhanced EBV reactivation. In summary, EBV BGLF2 interacts with Tyk2, inhibiting Tyk2, STAT1, and STAT3 phosphorylation and impairs type I IFN signaling; BGLF2 also counteracts the ability of IFN-α to suppress EBV reactivation. IMPORTANCE Type I interferons are important for controlling virus infection. We have found that the Epstein-Barr virus (EBV) BGLF2 tegument protein binds to a protein in the type I interferon signaling pathway Tyk2 and inhibits the expression of genes induced by type I interferons. Treatment of EBV-infected cells with type I interferon inhibits reactivation of the virus, while expression of EBV BGLF2 reduces the ability of type I interferon to inhibit virus reactivation. Thus, a tegument protein delivered to cells during virus infection inhibits the host’s antiviral response and promotes virus reactivation of latently infected cells. Therefore, EBV BGLF2 might protect virus-infected cells from the type I interferon response in cells undergoing lytic virus replication.

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