title: Primate-specific miR-576-3p sets host defense signalling threshold.
abstract: MicroRNAs (miRNAs) have been shown to regulate viral infection, but the miRNAs that target intracellular sensors and adaptors of innate immunity have not been fully uncovered. Here we conduct an miRNA mimic screen and validation with miRNA inhibitors in cells infected with vesicular stomatitis virus (VSV) to identify miRNAs that regulate viral-host interactions. We identify miR-576-3p as a robust regulator of infection by VSV and other RNA and DNA viruses. While an miR-576-3p mimic sensitizes cells to viral replication, inhibition of endogenous miR-576-3p prevents infection. miR-576-3p is induced by IRF3 concomitantly with interferon and targets STING, MAVS and TRAF3, which are critical factors for interferon expression. Interestingly, miR-576-3p and its binding sites are primate-specific and miR-576-3p levels are reduced in inflammatory diseases. These findings indicate that induction of miR-576-3p by IRF3 triggers a feedback mechanism to reduce interferon expression and set an antiviral response threshold to likely avoid excessive inflammation.
authors.affiliation: Departments of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9039, USA.
authors.forename: Melanie L
authors.initials: ML
authors.lastname: Yarbrough
authors.affiliation: Departments of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9039, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Departments of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9039, USA.
authors.forename: Ramanavelan
authors.initials: R
authors.lastname: Sakthivel
authors.affiliation: Department of Genetics and Genomic Sciences, Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York 10029-6574, USA.
authors.forename: Christian V
authors.initials: CV
authors.lastname: Forst
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9039, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Posner
authors.affiliation: Department of Cell Biology and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
authors.forename: Glen N
authors.initials: GN
authors.lastname: Barber
authors.affiliation: Departments of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9039, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: White
authors.affiliation: Departments of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9039, USA.
authors.forename: Beatriz M A
authors.initials: BM
authors.lastname: Fontoura
mesh_terms: D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001980:Bronchi / Q000821:virology; D017173:Caenorhabditis elegans; D002470:Cell Survival; D002522:Chlorocebus aethiops; D004285:Dogs; D004847:Epithelial Cells / Q000821:virology; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D007372:Interferons / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D008565:Membrane Proteins / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism; D014709:Vero Cells; D018116:Vesiculovirus / Q000276:immunology*; D000099197:STING Protein
chemical_list: D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; D050838:Interferon Regulatory Factor-3; D007372:Interferons; D008565:Membrane Proteins; D035683:MicroRNAs; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D048008:TNF Receptor-Associated Factor 3; C494232:IRF3 protein, human; C505371:MAVS protein, human; C000590114:MIRN576 microRNA, human; C532857:STING1 protein, human; D000099197:STING Protein; C090656:TRAF3 protein, human