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Human microRNA-30 inhibits influenza virus infection by suppressing the expression of SOCS1, SOCS3, and NEDD4.

ABSTRACT: Influenza A virus (IAV) has evolved multiple mechanisms to compromise type I interferon (IFN) responses. The antiviral function of IFN is mainly exerted by activating the JAK/STAT signalling and subsequently inducing IFN-stimulated gene (ISG) production. However, the mechanism by which IAV combat the type I IFN signalling pathway is not fully elucidated. In this study, we explored the roles of human microRNAs modulated by IAV infection in type I IFN responses. We demonstrated that microRNA-30 (miR-30) family members were downregulated by IAV infection. Our data showed that the forced expression of miR-30 family members inhibited IAV proliferation, while miR-30 family member inhibitors promoted IAV proliferation. Mechanistically, we found that miR-30 family members targeted and reduced SOCS1 and SOCS3 expression, and thus relieved their inhibiting effects on IFN/JAK/STAT signalling pathway. In addition, miR-30 family members inhibited the expression of NEDD4, a negative regulator of IFITM3, which is important for host defence against influenza viruses. Our findings suggest that IAV utilises a novel strategy to restrain host type I IFN-mediated antiviral immune responses by decreasing the expression of miR-30 family members, and add a new way to understand the mechanism of immune escape caused by influenza viruses.

SUBMITTER: Lin X

PROVIDER: S-EPMC7162240 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Human microRNA-30 inhibits influenza virus infection by suppressing the expression of SOCS1, SOCS3, and NEDD4.

Lin Xian X Yu Shiman S Ren Peilei P Sun Xiaomei X Jin Meilin M

Cellular microbiology 20191226 5

Influenza A virus (IAV) has evolved multiple mechanisms to compromise type I interferon (IFN) responses. The antiviral function of IFN is mainly exerted by activating the JAK/STAT signalling and subsequently inducing IFN-stimulated gene (ISG) production. However, the mechanism by which IAV combat the type I IFN signalling pathway is not fully elucidated. In this study, we explored the roles of human microRNAs modulated by IAV infection in type I IFN responses. We demonstrated that microRNA-30 (m ...[more]

PMID: 31876380

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Project description:Recent studies have reported that host microRNAs (miRNAs) regulate infections by several types of viruses via various mechanisms and that inhibition of the miRNA processing factors enhances or prevents viral infection. However, it has not been clarified whether these effects of miRNAs extend to adenovirus (Ad) infection. Here we show that miR-27a and -b efficiently inhibit infection with an Ad via the downregulation of SNAP25 and TXN2, which are members of the SNARE proteins and the thioredoxin family, respectively. Approximately 80% reductions in Ad genomic copy number were found in cells transfected with miR-27a/b mimics, whereas there were approximately 2.5- to 5-fold larger copy numbers of the Ad genome following transfection with miR-27a/b inhibitors. Microarray gene expression analysis and in silico analysis demonstrated that SNAP25 and TXN2 are target genes of miR-27a/b. A reporter assay using plasmids containing the 3' untranslated regions of the SNAP25 and TXN2 genes showed that miR-27a/b directly suppressed SNAP25 and TXN2 expression through posttranscriptional gene silencing. Knockdown of SNAP25 led to a significant inhibition of Ad entry into cells. Knockdown of TXN2 induced cell cycle arrest at G1 phase, leading to a reduction in Ad replication. In addition, overexpression of Ad-encoded small noncoding RNAs (VA-RNAs) restored the miR-27a/b-mediated reduction in infection level with a VA-RNA-lacking Ad mutant due to the VA-RNA-mediated inhibition of miR-27a/b expression. These results indicate that miR-27a and -b suppress SNAP25 and TXN2 expression via posttranscriptional gene silencing, leading to efficient suppression of Ad infection.IMPORTANCE Adenovirus (Ad) is widely used as a platform for replication-incompetent Ad vectors (Adv) and replication-competent oncolytic Ad (OAd) in gene therapy and virotherapy. Regulation of Ad infection is highly important for efficient gene therapies using both Adv and OAd. In this study, we demonstrate that miR-27a and -b, which are widely expressed in host cells, suppress SNAP25 and TXN2 expression through posttranscriptional gene silencing. Suppression of SNAP25 and TXN2 expression leads to inhibition of Ad entry into cells and to cell cycle arrest, respectively, leading to efficient suppression of Ad infection. Our findings provide important clues to the improvement of gene therapies using both Adv and OAd.

Dataset Information

Human microRNA-30 inhibits influenza virus infection by suppressing the expression of SOCS1, SOCS3, and NEDD4.

Publications

Human microRNA-30 inhibits influenza virus infection by suppressing the expression of SOCS1, SOCS3, and NEDD4.

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