000219460 001__ 219460
000219460 005__ 20180913063749.0
000219460 0247_ $$2doi$$a10.1371/journal.pbio.1002364
000219460 022__ $$a1545-7885
000219460 02470 $$2ISI$$a000373038200003
000219460 037__ $$aARTICLE
000219460 245__ $$aAn Interferon Regulated MicroRNA Provides Broad Cell-Intrinsic Antiviral Immunity through Multihit Host-Directed Targeting of the Sterol Pathway
000219460 260__ $$aSan Francisco$$bPublic Library Science$$c2016
000219460 269__ $$a2016
000219460 300__ $$a35
000219460 336__ $$aJournal Articles
000219460 520__ $$aIn 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.
000219460 700__ $$aRobertson, Kevin A.$$uUniv Edinburgh, Div Pathway Med, Edinburgh, Midlothian, Scotland
000219460 700__ $$aHsieh, Wei Yuan$$uUniv Edinburgh, Div Pathway Med, Edinburgh, Midlothian, Scotland
000219460 700__ $$aForster, Thorsten$$uUniv Edinburgh, Div Pathway Med, Edinburgh, Midlothian, Scotland
000219460 700__ $$0246519$$aBlanc, Mathieu$$g225934$$uUniv Edinburgh, Div Pathway Med, Edinburgh, Midlothian, Scotland
000219460 700__ $$aLu, Hongjin$$uUniv Edinburgh, Div Pathway Med, Edinburgh, Midlothian, Scotland
000219460 700__ $$aCrick, Peter J.$$uSwansea Univ, Coll Med, Inst Mass Spectrometry, Grove Bldg,Singleton Pk, Swansea, W Glam, Wales
000219460 700__ $$aYutuc, Eylan$$uSwansea Univ, Coll Med, Inst Mass Spectrometry, Grove Bldg,Singleton Pk, Swansea, W Glam, Wales
000219460 700__ $$aWatterson, Steven$$uUniv Edinburgh, Div Pathway Med, Edinburgh, Midlothian, Scotland
000219460 700__ $$aMartin, Kimberly$$uUniv Edinburgh, Div Pathway Med, Edinburgh, Midlothian, Scotland
000219460 700__ $$aGriffiths, Samantha J.$$uUniv Edinburgh, Div Pathway Med, Edinburgh, Midlothian, Scotland
000219460 700__ $$aEnright, Anton J.$$uEMBL European Bioinformat Inst, Wellcome Trust Genome Campus, Cambridge, England
000219460 700__ $$aYamamoto, Mami$$uUniv Edinburgh, Div Pathway Med, Edinburgh, Midlothian, Scotland
000219460 700__ $$aPradeepa, Madapura M.$$uWestern Gen Hosp, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland
000219460 700__ $$aLennox, Kimberly A.$$uIntegrated DNA Technol, Coralville, IA USA
000219460 700__ $$aBehlke, Mark A.$$uIntegrated DNA Technol, Coralville, IA USA
000219460 700__ $$aTalbot, Simon$$uUniv Edinburgh, Div Pathway Med, Edinburgh, Midlothian, Scotland
000219460 700__ $$aHaas, Juergen$$uUniv Edinburgh, Div Pathway Med, Edinburgh, Midlothian, Scotland
000219460 700__ $$aDoelken, Lars$$uUniv Cambridge, Dept Med, Cambridge CB2 2QQ, England
000219460 700__ $$aGriffiths, William J.$$uSwansea Univ, Coll Med, Inst Mass Spectrometry, Grove Bldg,Singleton Pk, Swansea, W Glam, Wales
000219460 700__ $$aWang, Yuqin$$uSwansea Univ, Coll Med, Inst Mass Spectrometry, Grove Bldg,Singleton Pk, Swansea, W Glam, Wales
000219460 700__ $$aAngulo, Ana$$uInst Invest Biomed August Pi & Sunyer, Barcelona, Spain
000219460 700__ $$aGhazal, Peter$$uUniv Edinburgh, Div Pathway Med, Edinburgh, Midlothian, Scotland
000219460 773__ $$j14$$k3$$qe1002364$$tPlos Biology
000219460 909C0 $$0252451$$pGHI$$xU11270
000219460 909CO $$ooai:infoscience.tind.io:219460$$pSV$$particle
000219460 937__ $$aEPFL-ARTICLE-219460
000219460 973__ $$aEPFL$$rREVIEWED$$sPUBLISHED
000219460 980__ $$aARTICLE