Herpes simplex virus‐1 induces expression of a novel MxA isoform that enhances viral replication

Ku, Chia-Chi; Che, Xibing; Reichelt, Mike; Rajamani, Jaya; Schaap-Nutt, Anne; Huang, Keliang; Sommer, Marvin; Chen, Yi-Shun; Chen, Yiyuan; Arvin, Ann M.

doi:10.1038/icb.2010.83

Cited by 49 publications

(34 citation statements)

References 40 publications

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“…Similarly, in the case of MxA, the appearance of exclusion isoforms was observed concurrently with a reduction in the amount of the canonical (inclusion) isoform (Fig 3C). This resembles a shift in the splicing pattern previously described for herpes virus infection, in which an MxA isoform supports instead of restricting viral infection [40]. Together, these observations suggest a model in which DENV infection alters cellular splicing patterns leading to changes in isoform abundance of antiviral factors, which could facilitate viral replication.…”

Section: Resultssupporting

confidence: 79%

The Dengue Virus NS5 Protein Intrudes in the Cellular Spliceosome and Modulates Splicing

et al. 2016

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Dengue virus NS5 protein plays multiple functions in the cytoplasm of infected cells, enabling viral RNA replication and counteracting host antiviral responses. Here, we demonstrate a novel function of NS5 in the nucleus where it interferes with cellular splicing. Using global proteomic analysis of infected cells together with functional studies, we found that NS5 binds spliceosome complexes and modulates endogenous splicing as well as minigene-derived alternative splicing patterns. In particular, we show that NS5 alone, or in the context of viral infection, interacts with core components of the U5 snRNP particle, CD2BP2 and DDX23, alters the inclusion/exclusion ratio of alternative splicing events, and changes mRNA isoform abundance of known antiviral factors. Interestingly, a genome wide transcriptome analysis, using recently developed bioinformatics tools, revealed an increase of intron retention upon dengue virus infection, and viral replication was improved by silencing specific U5 components. Different mechanistic studies indicate that binding of NS5 to the spliceosome reduces the efficiency of pre-mRNA processing, independently of NS5 enzymatic activities. We propose that NS5 binding to U5 snRNP proteins hijacks the splicing machinery resulting in a less restrictive environment for viral replication.

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Section: Resultssupporting

confidence: 79%

The Dengue Virus NS5 Protein Intrudes in the Cellular Spliceosome and Modulates Splicing

et al. 2016

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“…All 10 of these isoforms were generated through alternative splicing [25]. The IFN-α induced 76KDa MxA showed antiviral activity against herpes simplex virus 1 (HSV-1), while a variant MxA (produced from an alternatively spliced transcript) propagated HSV-1 [26]. Alternative splicing variants in occludin 1 determined the susceptibility to HCV infection and may be associated with the outcome of the infection [27].…”

Section: Discussionmentioning

confidence: 99%

A functional genomic screen reveals novel host genes that mediate interferon-alpha’s effects against hepatitis C virus

Zhao

Lin

Kumthip

et al. 2012

Journal of Hepatology

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Background & Aims The precise mechanisms by which IFN exerts its antiviral effect against HCV have not yet been elucidated. We sought to identify host genes that mediate the antiviral effect of IFN-α by conducting a whole-genome siRNA library screen. Methods High throughput screening was performed using an HCV genotype 1b replicon, pRep-Feo. Those pools with replicate robust Z scores ≥ 2.0 entered secondary validation in full-length OR6 replicon cells. Huh7.5.1 cells infected with JFH1 were then used to validate the rescue efficacy of selected genes for HCV replication under IFN-α treatment. Results We identified and confirmed 93 human genes involved in the IFN-α anti-HCV effect using a whole-genome siRNA library. Gene ontology analysis revealed that mRNA processing (23 genes, P=2.756e-22), translation initiation (9 genes, P=2.42e-6), and IFN signaling (5 genes, P=1.00e-3) were the most enriched functional groups. Nine genes were components of U4/U6.U5 tri-snRNP. We confirmed that silencing squamous cell carcinoma antigen recognized by T cells (SART1), a specific factor of tri-snRNP, abrogates IFN-α's suppressive effects against HCV in both replicon cells and JFH1 infectious cells. We further found that SART1 was not an IFN-α inducible, and its anti-HCV effector in the JFH1 infectious model was through regulation of interferon stimulated genes (ISGs) with or without IFN-α. Conclusions We identified 93 genes that mediate the anti-HCV effect of IFN-α through genome-wide siRNA screening; 23 and 9 genes were involved in mRNA processing and translation initiation, respectively. These findings reveal an unexpected role for mRNA processing in generation of the antiviral state, and suggest a new avenue for therapeutic development in HCV.

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“…By perturbing the functions of certain cellular proteins, the virus can greatly facilitate its replication [14], and this is presumed to be the case with HSV-1 infection [15]. Thus, it is reasonable to speculate that an HSV-1-encoded miRNA not only regulates viral gene expression but also has the potential to regulate the expression of host cell genes as has been demonstrated for HCMV miRNA [16].…”

mentioning

confidence: 99%

A microRNA encoded by HSV-1 inhibits a cellular transcriptional repressor of viral immediate early and early genes

Guo²,

Zhang

et al. 2013

Sci. China Life Sci.

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Viral microRNAs are one component of the RNA interference phenomenon generated during viral infection. They were first identified in the Herpesviridae family, where they were found to regulate viral mRNA translation. In addition, prior work has suggested that Kaposi's sarcoma-associated herpesvirus (KSHV) is capable of regulating cellular gene transcription by miRNA. We demonstrate that a miRNA, hsv1-mir-H27, encoded within the genome of herpes simplex virus 1 (HSV-1), targets the mRNA of the cellular transcriptional repressor Kelch-like 24 (KLHL24) that inhibits transcriptional efficiency of viral immediate-early and early genes. The viral miRNA is able to block the expression of KLHL24 in cells infected by HSV-1. Our discovery reveals an effective viral strategy for evading host cell defenses and supporting the efficient replication and proliferation of HSV-1.

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Herpes simplex virus‐1 induces expression of a novel MxA isoform that enhances viral replication

Cited by 49 publications

References 40 publications

The Dengue Virus NS5 Protein Intrudes in the Cellular Spliceosome and Modulates Splicing

The Dengue Virus NS5 Protein Intrudes in the Cellular Spliceosome and Modulates Splicing

A functional genomic screen reveals novel host genes that mediate interferon-alpha’s effects against hepatitis C virus

A microRNA encoded by HSV-1 inhibits a cellular transcriptional repressor of viral immediate early and early genes

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