Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China; University of Chinese Academy of Sciences, Beijing, China.
Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
Dev Comp Immunol. 2021 Feb;115:103876. doi: 10.1016/j.dci.2020.103876. Epub 2020 Sep 26.
In mammals, cyclic GMP-AMP synthase (cGAS) is a crucial cytosolic DNA sensor responsible for activating the interferon (IFN) response. A cGAS-like (cGASL) gene was previously identified from grass carp Ctenopharyngodon idellus, which is evolutionarily closest to cGAS but not a true ortholog of cGAS. Here, we found that grass carp cGASL targets mitochondrial antiviral signaling protein (MAVS) for autophagic degradation to negatively regulate fish IFN response. Firstly, the transcriptional level of cellular cgasl was upregulated by poly I:C stimulation, and overexpression of cGASL significantly decreased poly I:C- and MAVS-induced promoter activities and transcriptional levels of IFN and IFN-stimulated genes (ISGs). In addition, cGASL associated with MAVS and prompted autophagic degradation of MAVS in a dose-dependent manner. Finally, overexpression of cGASL attenuated MAVS-mediated cellular antiviral response. These results collectively indicate that cGASL negatively regulates fish IFN response by triggering autophagic degradation of MAVS.
在哺乳动物中，环鸟苷酸-腺苷酸合酶（cGAS）是一种重要的细胞质 DNA 传感器，负责激活干扰素（IFN）反应。先前从草鱼（Ctenopharyngodon idellus）中鉴定出一种 cGAS 样（cGASL）基因，它在进化上与 cGAS 最为接近，但不是 cGAS 的真正同源物。在这里，我们发现草鱼 cGASL 靶向线粒体抗病毒信号蛋白（MAVS）进行自噬降解，以负调控鱼类 IFN 反应。首先，细胞 cgasl 的转录水平被 poly I:C 刺激上调，过表达 cGASL 显著降低了 poly I:C 和 MAVS 诱导的启动子活性和 IFN 和 IFN 刺激基因（ISGs）的转录水平。此外，cGASL 与 MAVS 相关，并以剂量依赖的方式促使 MAVS 发生自噬降解。最后，过表达 cGASL 减弱了 MAVS 介导的细胞抗病毒反应。这些结果共同表明，cGASL 通过触发 MAVS 的自噬降解来负调控鱼类 IFN 反应。
