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

Kevin A. Robertson, Wei Yuan Hsieh, Thorsten Forster, Mathieu Blanc, Hongjin Lu, Peter J. Crick, Eylan Yutuc, Steven Watterson, Kimberly Martin, Samantha J. Griffiths, Anton J. Enright, Mami Yamamoto, Madapura M. Pradeepa, Kimberly A. Lennox, Mark A. Behlke, Simon Talbot, Jürgen Haas, Lars Dölken, William J. Griffiths, Yuqin WangAna Angulo, Peter Ghazal, Hidde L Ploegh

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Abstract

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.
Original languageEnglish
Article numbere1002364
Pages (from-to)1-35
Number of pages35
JournalPLoS Biology
Volume14
Issue number3
DOIs
Publication statusPublished - 3 Mar 2016

Keywords

  • sterol
  • cholesterol
  • immune
  • innate
  • microrna

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    Robertson, K. A., Hsieh, W. Y., Forster, T., Blanc, M., Lu, H., Crick, P. J., ... Ploegh, H. L. (Ed.) (2016). An Interferon Regulated MicroRNA Provides Broad Cell-Intrinsic Antiviral Immunity through Multihit Host-Directed Targeting of the Sterol Pathway. PLoS Biology, 14(3), 1-35. [e1002364]. https://doi.org/10.1371/journal.pbio.1002364