An interferon regulated microRNA provides cell-intrinsec anti-viral immunity through multihit host-directed targeting of the sterol pathway

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...

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Bibliographic Details
Authors: Robertson, Kevin A., Hsieh, Wei Yuan, Forster, Thorsten, Blanc, Mathieu, Lu, Hongjin, Crick, Peter J., Yutuc, Eylan, Watterson, Steven, Martin, Kimberly, Griffiths, Samantha J., Enright, Anton J., Yamamoto, Mami, Pradeepa, Madapura M., Lennox, Kimberly A., Behlke, Mark A., Talbot, Simon, Haas, Jürgen, Dolken, Lars, Griffiths, William J., Wang, Yuqin, Angulo Aguado, Ana, Ghazal, Peter
Format: article
Status:Published version
Publication Date:2016
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/112010
Online Access:https://hdl.handle.net/2445/112010
Access Level:Open access
Keyword:Interferó
Colesterol
Biosíntesi
Micro RNAs
Interferon
Cholesterol
Biosynthesis
MicroRNAs
Description
Summary: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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