Zheng Qingliang, Hou Jin, Zhou Ye, Yang Yingyun, Cao Xuetao
National Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; and.
National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China
J Immunol. 2016 Feb 1;196(3):1317-26. doi: 10.4049/jimmunol.1502134. Epub 2015 Dec 23.
Upon recognition of viral components by pattern recognition receptors, including TLRs and retinoic acid-inducible gene I-like helicases, cells are activated to produce type I IFN, which plays key roles in host antiviral innate immune response. However, excessive IFN production may induce immune disorders, and the mechanisms responsible for the regulation of type I IFN production have attracted much attention. Furthermore, type I IFN activates the downstream IFN/JAK/STAT pathway to modulate expression of a set of genes against viral infection, but whether these genes can feedback regulate type I IFN production is poorly understood. In this study, by screening the microRNAs modulated by viral infection in macrophages, we identified that microRNA (miR)-27a was significantly downregulated via the IFN/JAK/STAT1/runt-related transcription factor 1 pathway. Inducible downregulation of miR-27a, in turn, negatively regulated vesicular stomatitis virus-triggered type I IFN production, thus promoting vesicular stomatitis virus replication in macrophages. Mechanistically, we found that miR-27a directly targeted sialic acid-binding Ig-like lectin (Siglec)1 and E3 ubiquitin ligase tripartite motif-containing protein 27 (TRIM27), both of which were previously verified as negative regulators of type I IFN production. Furthermore, we constructed "Sponge" transgenic mice against miR-27a expression and found that Siglec1 and TRIM27 expression were elevated whereas type I IFN production was inhibited and viral replication was aggregated in vivo. Therefore, type I IFN-induced downregulation of miR-27a can upregulate Siglec1 and TRIM27 expression, feedback inhibiting type I IFN production in antiviral innate response. Our study outlines a new negative way to feedback regulate type I IFN production.
模式识别受体（包括Toll样受体（TLR）和视黄酸诱导基因I样解旋酶）识别病毒成分后，细胞被激活以产生I型干扰素，其在宿主抗病毒固有免疫反应中起关键作用。然而，过量的干扰素产生可能会引发免疫紊乱，且负责调节I型干扰素产生的机制已备受关注。此外，I型干扰素激活下游的干扰素/Janus激酶/信号转导子和转录激活子（IFN/JAK/STAT）通路，以调节一组抗病毒感染基因的表达，但这些基因是否能反馈调节I型干扰素的产生却知之甚少。在本研究中，通过筛选巨噬细胞中受病毒感染调节的微小RNA，我们发现微小RNA（miR）-27a通过IFN/JAK/STAT1/ runt相关转录因子1通路显著下调。反过来，miR-27a的可诱导下调负向调节水疱性口炎病毒引发的I型干扰素产生，从而促进水疱性口炎病毒在巨噬细胞中的复制。从机制上讲，我们发现miR-27a直接靶向唾液酸结合免疫球蛋白样凝集素（Siglec）1和E3泛素连接酶含三联基序蛋白27（TRIM27），这两者先前均被证实为I型干扰素产生的负调节因子。此外，我们构建了针对miR-27a表达的“海绵”转基因小鼠，发现Siglec1和TRIM27的表达升高，而I型干扰素的产生受到抑制，且病毒复制在体内聚集。因此，I型干扰素诱导的miR-27a下调可上调Siglec1和TRIM27的表达，在抗病毒固有反应中反馈抑制I型干扰素的产生。我们的研究概述了一种反馈调节I型干扰素产生的新的负向方式。
