title: Type I IFN-Inducible Downregulation of MicroRNA-27a Feedback Inhibits Antiviral Innate Response by Upregulating Siglec1/TRIM27.
abstract: Upon recognition of viral components by pattern recognition receptors, including TLRs and retinoic acid-inducible gene I-like helicases, cells are activated to produce type I IFN, which plays key roles in host antiviral innate immune response. However, excessive IFN production may induce immune disorders, and the mechanisms responsible for the regulation of type I IFN production have attracted much attention. Furthermore, type I IFN activates the downstream IFN/JAK/STAT pathway to modulate expression of a set of genes against viral infection, but whether these genes can feedback regulate type I IFN production is poorly understood. In this study, by screening the microRNAs modulated by viral infection in macrophages, we identified that microRNA (miR)-27a was significantly downregulated via the IFN/JAK/STAT1/runt-related transcription factor 1 pathway. Inducible downregulation of miR-27a, in turn, negatively regulated vesicular stomatitis virus-triggered type I IFN production, thus promoting vesicular stomatitis virus replication in macrophages. Mechanistically, we found that miR-27a directly targeted sialic acid-binding Ig-like lectin (Siglec)1 and E3 ubiquitin ligase tripartite motif-containing protein 27 (TRIM27), both of which were previously verified as negative regulators of type I IFN production. Furthermore, we constructed "Sponge" transgenic mice against miR-27a expression and found that Siglec1 and TRIM27 expression were elevated whereas type I IFN production was inhibited and viral replication was aggregated in vivo. Therefore, type I IFN-induced downregulation of miR-27a can upregulate Siglec1 and TRIM27 expression, feedback inhibiting type I IFN production in antiviral innate response. Our study outlines a new negative way to feedback regulate type I IFN production.
authors.affiliation: National Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; and.
authors.forename: Qingliang
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China caoxt@immunol.org houjinsmmu@126.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Hou
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Ye
authors.identifier: http://orcid.org/0000-0002-8780-0099
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: National Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; and.
authors.forename: Yingyun
authors.initials: Y
authors.lastname: Yang
authors.affiliation: National Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; and National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China caoxt@immunol.org houjinsmmu@126.com.
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000276:immunology; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D025461:Feedback, Physiological / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D015151:Immunoblotting; D047468:Immunoprecipitation; D007370:Interferon Type I / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000276:immunology*; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D018353:Rhabdoviridae Infections / Q000276:immunology* / Q000378:metabolism; D063267:Sialic Acid Binding Ig-like Lectin 1 / Q000096:biosynthesis* / Q000276:immunology; D014162:Transfection; D044767:Ubiquitin-Protein Ligases; D015854:Up-Regulation; D018116:Vesiculovirus / Q000276:immunology; D000070584:Tripartite Motif Proteins
chemical_list: D004268:DNA-Binding Proteins; D007370:Interferon Type I; D035683:MicroRNAs; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D063267:Sialic Acid Binding Ig-like Lectin 1; D044767:Ubiquitin-Protein Ligases; C540674:Mirn27 microRNA, mouse; C571167:Siglec1 protein, mouse; C489296:Trim27 protein, mouse; D000070584:Tripartite Motif Proteins