| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
,
* Institute of Immunology, Tsinghua University School of Medicine, Beijing, China;
National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China;
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China; and
Department of Medical Genetics, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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-
B-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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the National Natural Science Foundation of China (30721091), the National 115 Key Project for HBV Research (2008ZX10002-008), and the National Key Basic Research Program of China (2007CB512403).
2 J.H., P.W., and L.L. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Xuetao Cao, National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433. E-mail address: caoxt{at}public3.sta.net.cn; or Dr. Zhugang Wang, Department of Medical Genetics, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. E-mail address: zhugangw{at}vip.163.com
4 Abbreviations used in this paper: RIG-I, retinoic acid-inducible gene I; RLH, RIG-I-like helicase; miRNA, microRNA; VSV, vesicular stomatitis virus; CARD, caspase recruitment domain; FADD, Fas-associated death domain-containing protein; TRAF, TNFR-associated factor; MyD88, myeloid differentiation factor 88; UTR, untranslational region; IRAK, IL-1R-associated kinase; TCID50, 50% tissue culture infectious dose; poly(IC), polyinosinic-polycytidylic acid; PDTC, pyrrolidinecarbodithoic acid; BMDC, bone marrow-derived dendritic cell; MOI, multiplicity of infection; TRIF, Toll-IL-1R domain-containing adaptor inducing IFN-β; q-RT-PCR, quantitative RT-PCR; MEF, mouse embryonic fibroblast.
5 The online version of this article contains supplemental material.
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
