An Interferon Regulated MicroRNA Provides Broad Cell-Intrinsic Antiviral Immunity through Multihit Host-Directed Targeting of the Sterol Pathway.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101183755 Publication Model: eCollection Cited Medium: Internet ISSN: 1545-7885 (Electronic) Linking ISSN: 15449173 NLM ISO Abbreviation: PLoS Biol Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, [2003]-

Interferon Regulatory Factor-1/*metabolism ; Interferons/*physiology ; MicroRNAs/*metabolism ; Sterols/*biosynthesis ; Virus Diseases/*immunology; Animals ; Mice, Inbred C57BL

In invertebrates, small interfering RNAs are at the vanguard of cell-autonomous antiviral immunity. In contrast, antiviral mechanisms initiated by interferon (IFN) signaling predominate in mammals. Whilst mammalian IFN-induced miRNA are known to inhibit specific viruses, it is not known whether host-directed microRNAs, downstream of IFN-signaling, have a role in mediating broad antiviral resistance. By performing an integrative, systematic, global analysis of RNA turnover utilizing 4-thiouridine labeling of newly transcribed RNA and pri/pre-miRNA in IFN-activated macrophages, we identify a new post-transcriptional viral defense mechanism mediated by miR-342-5p. On the basis of ChIP and site-directed promoter mutagenesis experiments, we find the synthesis of miR-342-5p is coupled to the antiviral IFN response via the IFN-induced transcription factor, IRF1. Strikingly, we find miR-342-5p targets mevalonate-sterol biosynthesis using a multihit mechanism suppressing the pathway at different functional levels: transcriptionally via SREBF2, post-transcriptionally via miR-33, and enzymatically via IDI1 and SC4MOL. Mass spectrometry-based lipidomics and enzymatic assays demonstrate the targeting mechanisms reduce intermediate sterol pathway metabolites and total cholesterol in macrophages. These results reveal a previously unrecognized mechanism by which IFN regulates the sterol pathway. The sterol pathway is known to be an integral part of the macrophage IFN antiviral response, and we show that miR-342-5p exerts broad antiviral effects against multiple, unrelated pathogenic viruses such Cytomegalovirus and Influenza A (H1N1). Metabolic rescue experiments confirm the specificity of these effects and demonstrate that unrelated viruses have differential mevalonate and sterol pathway requirements for their replication. This study, therefore, advances the general concept of broad antiviral defense through multihit targeting of a single host pathway.

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G0901002 United Kingdom MRC_ Medical Research Council; BB/E010709/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; BB/D019621/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; WT066784/Z/02/Z United Kingdom WT_ Wellcome Trust; C20035 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; BB/H007849/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; BB/K019112/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; United Kingdom Wellcome Trust; BB/K003801/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; G1002523 United Kingdom MRC_ Medical Research Council

0 (Interferon Regulatory Factor-1)
0 (Irf1 protein, mouse)
0 (MicroRNAs)
0 (Mirn342 microRNA, mouse)
0 (Sterols)
9008-11-1 (Interferons)

Date Created: 20160304 Date Completed: 20160810 Latest Revision: 20220129

20240829

PMC4777525

10.1371/journal.pbio.1002364

26938778