Landscape of post-transcriptional gene regulation during hepatitis C virus infection

Schwerk, Johannes; Jarret, Abigail; Joslyn, Rochelle C; Savan, Ram

doi:10.1016/j.coviro.2015.02.006

Cited by 13 publications

(10 citation statements)

References 104 publications

(102 reference statements)

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“…HCV may also impact the expression landscape of host miRNAs and co-opt their functions to establish viral persistence and induce various pathological conditions in the liver (Schwerk et al . 2015). The exact roles and underlying mechanisms of cellular miRNAs in modulating HCV infection and associated liver diseases, nevertheless, remain to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-135a Modulates Hepatitis C Virus Genome Replication through Downregulation of Host Antiviral Factors

et al. 2018

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Cellular microRNAs (miRNAs) have been shown to modulate HCV infection via directly acting on the viral genome or indirectly through targeting the virus-associated host factors. Recently we generated a comprehensive map of HCV–miRNA interactions through genome-wide miRNA functional screens and transcriptomics analyses. Many previously unappreciated cellular miRNAs were identified to be involved in HCV infection, including miR-135a, a human cancer-related miRNA. In the present study, we investigated the role of miR-135a in regulating HCV life cycle and showed that it preferentially enhances viral genome replication. Bioinformatics-based integrative analyses and subsequent functional assays revealed three antiviral host factors, including receptor interacting serine/threonine kinase 2 (RIPK2), myeloid differentiation primary response 88 (MYD88), and C-X-C motif chemokine ligand 12 (CXCL12), as bona fide targets of miR-135a. These genes have been shown to inhibit HCV infection at the RNA replication stage. Our data demonstrated that repression of key host restriction factors mediated the proviral effect of miR-135a on HCV propagation. In addition, miR-135a hepatic abundance is upregulated by HCV infection in both cultured hepatocytes and human liver, likely mediating a more favorable environment for viral replication and possibly contributing to HCV-induced liver malignancy. These results provide novel insights into HCV–host interactions and unveil molecular pathways linking miRNA biology to HCV pathogenesis. Electronic supplementary material The online version of this article (10.1007/s12250-018-0055-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-135a Modulates Hepatitis C Virus Genome Replication through Downregulation of Host Antiviral Factors

et al. 2018

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“…A recent study shows that in addition to miR-146, miR-155 is also involved in regulation of chronic inflammation (21). Several excellent reviews discuss the roles of miRNAs in immune regulation and immune responses in more (5, 46–48) depth.…”

Section: Immune Regulation By Micrornasmentioning

confidence: 99%

Translating the Untranslated Region

Schwerk

Savan

2015

The Journal of Immunology

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Gene expression programs undergo constant regulation to quickly adjust to environmental stimuli that alter the physiological status of the cell, like cellular stress or infection. Gene expression is tightly regulated by multi-layered regulatory elements acting in both cis and trans. Post-transcriptional regulation of the 3′ untranslated region (3′ UTR) is a powerful regulatory process that determines the rate of protein translation from messenger RNA. Regulatory elements targeting the 3′ UTR comprise microRNAs, RNA-binding proteins and long non-coding RNAs, which dramatically alter the immune response. Here we provide an overview of our current understanding of post-transcriptional regulation of immune gene expression. The focus of this review will be on regulatory elements that target the 3′ UTR. We will delineate how the synergistic or antagonistic interactions of post-transcriptional regulators determine gene expression levels, and how dysregulation of 3′ UTR-mediated post-transcriptional control associates with human diseases.

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“…Full induction of this antiviral state requires hundreds of ISGs to be upregulated efficiently, and therefore cells must encode mechanisms to ensure their regulated expression. Such regulation can occur at both the transcriptional and post-transcriptional level (4-6). While several post-transcriptional controls of antiviral cytokines and signaling molecules have been defined, similar mechanisms that regulate ISG expression have been largely unexplored (5, 7).…”

Section: Introductionmentioning

confidence: 99%

The mRNA cap 2’O methyltransferase CMTR1 regulates the expression of certain interferon-stimulated genes

Williams

Gokhale

Snider

et al. 2020

Preprint

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AbstractType I interferons (IFN) initiate an antiviral state through a signal transduction cascade that leads to the induction of hundreds of IFN-stimulated genes (ISGs) to restrict viral infection. Recently, RNA modifications on both host and viral RNAs have been described as regulators of infection. However, the impact of host mRNA cap modifications on the IFN response and how this regulates viral infection is unknown. Here, we reveal that CMTR1, an ISG that catalyzes 2’O methylation of the first transcribed nucleotide in cellular mRNA (Cap 1), promotes the protein expression of specific ISGs that contribute to the antiviral response. Depletion of CMTR1 reduces the IFN-induced protein levels of ISG15, MX1, and IFITM1, without affecting their transcript abundance. However, CMTR1 depletion does not significantly affect the IFN-induced protein or transcript abundance of IFIT1 and IFIT3. Importantly, knockdown of IFIT1, which acts with IFIT3 to inhibit the translation of RNAs lacking Cap 1 2’O methylation, restores protein expression of ISG15, MX1, and IFITM1 in cells depleted of CMTR1. Finally, we found that CMTR1 plays a role in restricting RNA virus replication, likely by ensuring the expression of specific antiviral ISGs. Taken together, these data reveal that CMTR1 is required to establish an antiviral state by ensuring the protein expression of a subset of ISGs during the type I IFN response.ImportanceInduction of an efficient type I IFN response is important to control viral infection. We show that the host 2’O methyltransferase CMTR1 facilitates the protein expression of ISGs in human cells by preventing IFIT1 from inhibiting the translation of these mRNAs lacking cap 2’O methylation. Thus, CMTR1 promotes the IFN-mediated antiviral response.

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Landscape of post-transcriptional gene regulation during hepatitis C virus infection

Cited by 13 publications

References 104 publications

MicroRNA-135a Modulates Hepatitis C Virus Genome Replication through Downregulation of Host Antiviral Factors

MicroRNA-135a Modulates Hepatitis C Virus Genome Replication through Downregulation of Host Antiviral Factors

Translating the Untranslated Region

The mRNA cap 2’O methyltransferase CMTR1 regulates the expression of certain interferon-stimulated genes

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