State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China.
J Immunol. 2023 Sep 15;211(6):1006-1019. doi: 10.4049/jimmunol.2300214.
Liver X receptors (LXRs) are nuclear receptors involved in metabolism and the immune response. Different from mammalian LXRs, which include two isoforms, LXRα and LXRβ, only a single LXRα gene exists in the piscine genomes. Although a study has suggested that piscine LXR inhibits intracellular bacterial survival, the functions of piscine LXRα in viral infection are unknown. In this study, we show that overexpression of LXRα from grass carp (Ctenopharyngodon idellus), which is named as gcLXRα, increases host susceptibility to grass carp reovirus (GCRV) infection, whereas gcLXRα knockdown in CIK (C. idellus kidney) cells inhibits GCRV infection. Consistent with these functional studies, gcLXRα knockdown promotes the transcription of antiviral genes involved in the RIG-I-like receptor (RLR) antiviral signaling pathway, including IFN regulatory factor (IRF3) and the type I IFN IFN1. Further results show that gcLXRα knockdown induces the expression of CREB-binding protein (CBP), a transcriptional coactivator. In the knockdown of CBP, the inhibitory effect of gcLXRα knockdown in limiting GCRV infection is completely abolished. gcLXRα also interacts with IRF3 and CBP, which impairs the formation of the IRF3/CBP transcription complex. Moreover, gcLXRα heterodimerizes with RXRg, which cooperatively impair the transcription of the RLR antiviral signaling pathway and promote GCRV infection. Taken together, to our knowledge, our findings provide new insight into the functional correlation between nuclear receptor LXRα and the RLR antiviral signaling pathway, and they demonstrate that gcLXRα can impair the RLR antiviral signaling pathway and the production of type I IFN via forming gcLXRα/RXRg complexes and attenuating IRF3/CBP complexes.
肝 X 受体 (LXRs) 是参与代谢和免疫反应的核受体。与哺乳动物 LXRs 不同，哺乳动物 LXRs 包括两种异构体，LXRα 和 LXRβ，而鱼类基因组中仅存在单一的 LXRα 基因。尽管有研究表明鱼类 LXR 抑制细胞内细菌存活，但鱼类 LXRα 在病毒感染中的功能尚不清楚。在这项研究中，我们表明草鱼（Ctenopharyngodon idellus）的 LXRα 过表达（命名为 gcLXRα）增加了宿主对草鱼虹彩病毒（GCRV）感染的易感性，而在 CIK（草鱼肾脏）细胞中 gcLXRα 的敲低抑制了 GCRV 感染。与这些功能研究一致，gcLXRα 的敲低促进了参与 RIG-I 样受体 (RLR) 抗病毒信号通路的抗病毒基因的转录，包括干扰素调节因子 (IRF3) 和 I 型干扰素 IFN1。进一步的结果表明，gcLXRα 的敲低诱导了转录共激活因子 CREB 结合蛋白 (CBP) 的表达。在 CBP 的敲低中，gcLXRα 敲低在限制 GCRV 感染中的抑制作用完全被消除。gcLXRα 还与 IRF3 和 CBP 相互作用，破坏了 IRF3/CBP 转录复合物的形成。此外，gcLXRα 与 RXRg 异二聚化，共同损害 RLR 抗病毒信号通路的转录并促进 GCRV 感染。总之，据我们所知，我们的发现为核受体 LXRα 与 RLR 抗病毒信号通路之间的功能相关性提供了新的见解，并表明 gcLXRα 可以通过形成 gcLXRα/RXRg 复合物和削弱 IRF3/CBP 复合物来损害 RLR 抗病毒信号通路和 I 型 IFN 的产生。
