An Interferon Regulated MicroRNA Provides Broad Cell-Intrinsic Antiviral 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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| Published in | PLoS biology Vol. 14; no. 3; p. e1002364 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Public Library of Science
03.03.2016
Public Library of Science (PLoS) |
| Subjects | |
| Online Access | Get full text |
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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. |
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| AbstractList | 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. 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. An interferon-induced miRNA suppresses the sterol biosynthesis pathway via multiple targets, thereby helping establish broad cellular resistance to unrelated clinically significant viruses. How infected cells respond to a virus during the first minutes to hours after infection can determine whether a disease develops and influences the host’s long-term survival. In mammals, unlike plants and flies that use small RNAs to fight viral infections, virus-induced interferon responses are a critical early event resulting in broad protection against infection. Interferon is a secreted host protein that binds to receptors on the surface of infected and uninfected cells and activates biochemical pathways that profoundly change the expression of hundreds of cellular genes, including those encoding microRNAs. The antiviral functions of only a handful of these genes are understood, and it is not known how the majority contribute to broadly protect against many different viruses. In this study, we uncover an interferon-regulated microRNA (miR-342-5p) that contributes to broad host cell immunity against infection through the cholesterol biosynthesis pathway. We show that miR-342-5p does this through a multihit strategy, turning down the master regulator of sterol biosynthesis as well as several specifically targeted enzymes within the pathway. A wide range of viruses depend on a number of the metabolite side-branches of the sterol biosynthesis pathway for their replication. Notably, our study reveals that by utilising multihit targeting of key branch-points in a single pathway, miR-342-5p is able to inhibit the replication of unrelated, clinically significant pathogens ranging from Herpes to Flu viruses. 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. |
| Audience | Academic |
| Author | Crick, Peter J. Blanc, Mathieu Robertson, Kevin A. Yamamoto, Mami Watterson, Steven Pradeepa, Madapura M. Haas, Jürgen Ghazal, Peter Enright, Anton J. Griffiths, Samantha J. Dölken, Lars Talbot, Simon Martin, Kimberly Lennox, Kimberly A. Wang, Yuqin Hsieh, Wei Yuan Lu, Hongjin Griffiths, William J. Yutuc, Eylan Forster, Thorsten Angulo, Ana Behlke, Mark A. |
| AuthorAffiliation | 13 Immunology Unit, Department of Cell Biology, Immunology, and Neurosciences, Medical School, University of Barcelona, Barcelona, Spain 5 Northern Ireland Centre for Stratified Medicine, University of Ulster, C-Tric, Altnagelvin Campus, Londonderry, Ireland 2 SynthSys at Edinburgh University, The King’s Buildings, Edinburgh, United Kingdom 7 EMBL – European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom 10 Department of Medicine, University of Cambridge, Cambridge, United Kingdom 4 Institute of Mass Spectrometry, College of Medicine, Grove Building, Swansea University, Singleton Park, Swansea, United Kingdom 11 Institute of Virology, University of Würzburg, Würzburg, Germany Whitehead Institute, UNITED STATES 12 Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain 9 Integrated DNA Technologies, Coralville, Iowa, United States of America 3 École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland 6 Centre for Integrative Phys |
| AuthorAffiliation_xml | – name: 2 SynthSys at Edinburgh University, The King’s Buildings, Edinburgh, United Kingdom – name: 6 Centre for Integrative Physiology, Edinburgh, United Kingdom – name: 8 The Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, United Kingdom – name: 11 Institute of Virology, University of Würzburg, Würzburg, Germany – name: 7 EMBL – European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom – name: 13 Immunology Unit, Department of Cell Biology, Immunology, and Neurosciences, Medical School, University of Barcelona, Barcelona, Spain – name: 3 École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland – name: 9 Integrated DNA Technologies, Coralville, Iowa, United States of America – name: 12 Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain – name: 4 Institute of Mass Spectrometry, College of Medicine, Grove Building, Swansea University, Singleton Park, Swansea, United Kingdom – name: 1 Division of Pathway Medicine, University of Edinburgh, Edinburgh, United Kingdom – name: 10 Department of Medicine, University of Cambridge, Cambridge, United Kingdom – name: 5 Northern Ireland Centre for Stratified Medicine, University of Ulster, C-Tric, Altnagelvin Campus, Londonderry, Ireland – name: Whitehead Institute, UNITED STATES |
| Author_xml | – sequence: 1 givenname: Kevin A. surname: Robertson fullname: Robertson, Kevin A. – sequence: 2 givenname: Wei Yuan surname: Hsieh fullname: Hsieh, Wei Yuan – sequence: 3 givenname: Thorsten surname: Forster fullname: Forster, Thorsten – sequence: 4 givenname: Mathieu surname: Blanc fullname: Blanc, Mathieu – sequence: 5 givenname: Hongjin surname: Lu fullname: Lu, Hongjin – sequence: 6 givenname: Peter J. surname: Crick fullname: Crick, Peter J. – sequence: 7 givenname: Eylan surname: Yutuc fullname: Yutuc, Eylan – sequence: 8 givenname: Steven surname: Watterson fullname: Watterson, Steven – sequence: 9 givenname: Kimberly surname: Martin fullname: Martin, Kimberly – sequence: 10 givenname: Samantha J. surname: Griffiths fullname: Griffiths, Samantha J. – sequence: 11 givenname: Anton J. surname: Enright fullname: Enright, Anton J. – sequence: 12 givenname: Mami surname: Yamamoto fullname: Yamamoto, Mami – sequence: 13 givenname: Madapura M. surname: Pradeepa fullname: Pradeepa, Madapura M. – sequence: 14 givenname: Kimberly A. surname: Lennox fullname: Lennox, Kimberly A. – sequence: 15 givenname: Mark A. surname: Behlke fullname: Behlke, Mark A. – sequence: 16 givenname: Simon surname: Talbot fullname: Talbot, Simon – sequence: 17 givenname: Jürgen surname: Haas fullname: Haas, Jürgen – sequence: 18 givenname: Lars surname: Dölken fullname: Dölken, Lars – sequence: 19 givenname: William J. surname: Griffiths fullname: Griffiths, William J. – sequence: 20 givenname: Yuqin surname: Wang fullname: Wang, Yuqin – sequence: 21 givenname: Ana surname: Angulo fullname: Angulo, Ana – sequence: 22 givenname: Peter surname: Ghazal fullname: Ghazal, Peter |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26938778$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | COPYRIGHT 2016 Public Library of Science 2016 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Robertson KA, Hsieh WY, Forster T, Blanc M, Lu H, Crick PJ, et al. (2016) An Interferon Regulated MicroRNA Provides Broad Cell-Intrinsic Antiviral Immunity through Multihit Host-Directed Targeting of the Sterol Pathway. PLoS Biol 14(3): e1002364. doi:10.1371/journal.pbio.1002364 2016 Robertson et al 2016 Robertson et al 2016 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Robertson KA, Hsieh WY, Forster T, Blanc M, Lu H, Crick PJ, et al. (2016) An Interferon Regulated MicroRNA Provides Broad Cell-Intrinsic Antiviral Immunity through Multihit Host-Directed Targeting of the Sterol Pathway. PLoS Biol 14(3): e1002364. doi:10.1371/journal.pbio.1002364 |
| Copyright_xml | – notice: COPYRIGHT 2016 Public Library of Science – notice: 2016 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Robertson KA, Hsieh WY, Forster T, Blanc M, Lu H, Crick PJ, et al. (2016) An Interferon Regulated MicroRNA Provides Broad Cell-Intrinsic Antiviral Immunity through Multihit Host-Directed Targeting of the Sterol Pathway. PLoS Biol 14(3): e1002364. doi:10.1371/journal.pbio.1002364 – notice: 2016 Robertson et al 2016 Robertson et al – notice: 2016 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Robertson KA, Hsieh WY, Forster T, Blanc M, Lu H, Crick PJ, et al. (2016) An Interferon Regulated MicroRNA Provides Broad Cell-Intrinsic Antiviral Immunity through Multihit Host-Directed Targeting of the Sterol Pathway. PLoS Biol 14(3): e1002364. doi:10.1371/journal.pbio.1002364 |
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| DOI | 10.1371/journal.pbio.1002364 |
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| License | This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. Creative Commons Attribution License |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 MAB and KAL are employed by Integrated DNA Technologies, Inc., (IDT) which offers oligonucleotides for sale similar to some of the compounds described in the manuscript. IDT is however not a publicly traded company and these authors do not personally own any shares/equity in IDT. Conceived and designed the experiments: KAR PG MB. Performed the experiments: KAR WYH PJC EY YW WJG KM MY MMP SJG AA HL ST. Analyzed the data: KAR TF SW WJG AJE PG. Contributed reagents/materials/analysis tools: LD JH KAL MAB AJE MMP. Wrote the paper: KAR PG. |
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| Title | An Interferon Regulated MicroRNA Provides Broad Cell-Intrinsic Antiviral Immunity through Multihit Host-Directed Targeting of the Sterol Pathway |
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