TY - JOUR
T1 - Primate-specific miR-576-3p sets host defense signalling threshold
AU - Yarbrough, Melanie L.
AU - Zhang, Ke
AU - Sakthivel, Ramanavelan
AU - Forst, Christian V.
AU - Posner, Bruce A.
AU - Barber, Glen N.
AU - White, Michael A.
AU - Fontoura, Beatriz M.A.
N1 - Funding Information:
We thank Angela Diehl for outstanding illustration. Funding was provided by NIH R01 GM067159, R01 AI079110, R01 AI089539, CPRIT RP121003-RP120718-P2, T32-CA124334 and F32-AI091409.
Publisher Copyright:
© 2014 Macmillan Publishers Limited. All rights reserved.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84910052591&partnerID=8YFLogxK
U2 - 10.1038/ncomms5963
DO - 10.1038/ncomms5963
M3 - Article
C2 - 25232931
AN - SCOPUS:84910052591
SN - 2041-1723
VL - 5
JO - Nature communications
JF - Nature communications
M1 - 4963
ER -