title: Downregulation of microRNA miR-526a by enterovirus inhibits RIG-I-dependent innate immune response.
abstract: Retinoic acid-inducible gene I (RIG-I) is an intracellular RNA virus sensor that induces type I interferon-mediated host-protective innate immunity against viral infection. Although cylindromatosis (CYLD) has been shown to negatively regulate innate antiviral response by removing K-63-linked polyubiquitin from RIG-I, the regulation of its expression and the underlying regulatory mechanisms are still incompletely understood. Here we show that RIG-I activity is regulated by inhibition of CYLD expression mediated by the microRNA miR-526a. We found that viral infection specifically upregulates miR-526a expression in macrophages via interferon regulatory factor (IRF)-dependent mechanisms. In turn, miR-526a positively regulates virus-triggered type I interferon (IFN-I) production, thus suppressing viral replication, the underlying mechanism of which is the enhancement of RIG-I K63-linked ubiquitination by miR-526a via suppression of the expression of CYLD. Remarkably, virus-induced miR-526a upregulation and CYLD downregulation are blocked by enterovirus 71 (EV71) 3C protein, while ectopic miR-526a expression inhibits the replication of EV71 virus. The collective results of this study suggest a novel mechanism of the regulation of RIG-I activity during RNA virus infection by miR-526a and suggest a novel mechanism for the evasion of the innate immune response controlled by EV71.
  
  
  OBJECTIVE
  RNA virus infection upregulates the expression of miR-526a in macrophages through IRF-dependent pathways. In turn, miR-526a positively regulates virus-triggered type I IFN production and inhibits viral replication, the underlying mechanism of which is the enhancement of RIG-I K-63 ubiquitination by miR-526a via suppression of the expression of CYLD. Remarkably, virus-induced miR-526a upregulation and CYLD downregulation are blocked by enterovirus 71 (EV71) 3C protein; cells with overexpressed miR-526a were highly resistant to EV71 infection. The collective results of this study suggest a novel mechanism of the regulation of RIG-I activity during RNA virus infection by miR-526a and propose a novel mechanism for the evasion of the innate immune response controlled by EV71.
authors: Beijing Institute of Biotechnology, Beijing, China Institute of Health Science, School of Life Sciences, AnHui University, Hefei, Anhui, China.
authors: Changzhi
authors: C
authors: Xu
authors: Beijing Institute of Biotechnology, Beijing, China.
authors: Xiang
authors: X
authors: He
authors: Beijing Institute of Biotechnology, Beijing, China Institute of Health Science, School of Life Sciences, AnHui University, Hefei, Anhui, China.
authors: Zirui
authors: Z
authors: Zheng
authors: Beijing Institute of Biotechnology, Beijing, China.
authors: Zhe
authors: Z
authors: Zhang
authors: Beijing Institute of Biotechnology, Beijing, China.
authors: Congwen
authors: C
authors: Wei
authors: Beijing Institute of Biotechnology, Beijing, China.
authors: Kai
authors: K
authors: Guan
authors: Beijing Institute of Biotechnology, Beijing, China.
authors: Lihua
authors: L
authors: Hou
authors: Institute of Health Science, School of Life Sciences, AnHui University, Hefei, Anhui, China.
authors: Buchang
authors: B
authors: Zhang
authors: Institute of Health Science, School of Life Sciences, AnHui University, Hefei, Anhui, China.
authors: Lin
authors: L
authors: Zhu
authors: Department of Laboratory Medicine, General Hospital of Jinan Military Region, Jinan, Shandong, China.
authors: Yuan
authors: Y
authors: Cao
authors: Beijing Institute of Biotechnology, Beijing, China.
authors: Yanhong
authors: Y
authors: Zhang
authors: Beijing Institute of Biotechnology, Beijing, China.
authors: Ye
authors: Y
authors: Cao
authors: Beijing Institute of Biotechnology, Beijing, China.
authors: Shengli
authors: S
authors: Ma
authors: Beijing Institute of Biotechnology, Beijing, China.
authors: Penghao
authors: P
authors: Wang
authors: Beijing Institute of Biotechnology, Beijing, China Department of Laboratory Medicine, General Hospital of Jinan Military Region, Jinan, Shandong, China.
authors: Pingping
authors: P
authors: Zhang
authors: Beijing Institute of Biotechnology, Beijing, China.
authors: Quanbin
authors: Q
authors: Xu
authors: Beijing Institute of Biotechnology, Beijing, China.
authors: Youguo
authors: Y
authors: Ling
authors: Beijing Institute of Biotechnology, Beijing, China xyang@nic.bmi.ac.cn towall@yahoo.com.
authors: Xiao
authors: X
authors: Yang
authors: Beijing Institute of Biotechnology, Beijing, China xyang@nic.bmi.ac.cn towall@yahoo.com.
authors: Hui
authors: H
authors: Zhong
mesh_terms: D000086042:3C Viral Proteases; D000818:Animals; D002522:Chlorocebus aethiops; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000276:immunology; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000276:immunology; D000074749:Deubiquitinating Enzyme CYLD; D004285:Dogs; D029821:Enterovirus A, Human / Q000235:genetics* / Q000276:immunology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D007113:Immunity, Innate; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000821:virology; D061985:Madin Darby Canine Kidney Cells; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology; D025821:Polyubiquitin / Q000235:genetics / Q000276:immunology; D011971:Receptors, Immunologic; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000276:immunology; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics* / Q000276:immunology; D014779:Virus Replication
chemical_list: D007370:Interferon Type I; D035683:MicroRNAs; D011971:Receptors, Immunologic; D025521:Tumor Suppressor Proteins; D014764:Viral Proteins; D025821:Polyubiquitin; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases