MicroRNA-146a feedback inhibits RIG-I-dependent Type I IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2.
Upon recognition of viral components by pattern recognition receptors, including TLRs and retinoic acid-inducible gene I (RIG-I)- like helicases, cells are activated to produce type I IFN and proinflammatory cytokines. These pathways are tightly regulated by host to prevent inappropriate cellular response, but viruses can down-regulate these pathways for their survival. Recently, identification of negative regulators for cytoplasmic RNA-mediated antiviral signaling, especially the RIG-I pathway, attract much attention. However, there is no report about negative regulation of RIG-I antiviral pathway by microRNAs (miRNA) to date. We found that vesicular stomatitis virus (VSV) infection up-regulated miR-146a expression in mouse macrophages in TLR-myeloid differentiation factor 88-independent but RIG-I-NF-kappaB-dependent manner. In turn, miR-146a negatively regulated VSV-triggered type I IFN production, thus promoting VSV replication in macrophages. In addition to two known miR-146a targets, TRAF6 and IRAK1, we proved that IRAK2 was another target of miR-146a, which also participated in VSV-induced type I IFN production. Furthermore, IRAK1 and IRAK2 participated in VSV-induced type I IFN production by associating with Fas-associated death domain protein, an important adaptor in RIG-I signaling, in a VSV infection-inducible manner. Therefore, we demonstrate that miR-146a, up-regulated during viral infection, is a negative regulator of the RIG-I-dependent antiviral pathway by targeting TRAF6, IRAK1, and IRAK2.
Hou
Jin
J
Institute of Immunology, Tsinghua University School of Medicine, Beijing, China.
Wang
Pin
P
Lin
Li
L
Liu
Xingguang
X
Ma
Feng
F
An
Huazhang
H
Wang
Zhugang
Z
Cao
Xuetao
X
D000818:Animals; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D025461:Feedback, Physiological / Q000235:genetics* / Q000276:immunology; D007109:Immunity; D007370:Interferon Type I / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000037:antagonists & inhibitors; D015854:Up-Regulation / Q000187:drug effects; D054243:Vesicular Stomatitis / Q000235:genetics / Q000276:immunology; D018116:Vesiculovirus / Q000187:drug effects; D014777:Virus Diseases / Q000235:genetics / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects
D007370:Interferon Type I; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D048029:TNF Receptor-Associated Factor 6; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases