State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
University of Chinese Academy of Sciences, Beijing, China.
J Immunol. 2022 Mar 1;208(5):1189-1203. doi: 10.4049/jimmunol.2100962. Epub 2022 Jan 31.
The small HERC family currently comprises four members (HERC3-6) involved in the regulation of various physiological activities. Little is known about the role of HERCs in IFN response. In this study, we identify a novel fish HERC member, named crucian carp HERC7, as a negative regulator of fish IFN response. Genome-wide search of homologs and comprehensive phylogenetic analyses reveal that the small HERC family, apart from HERC3-6 that have been well-characterized in mammals, contains a novel HERC7 subfamily exclusively in nonmammalian vertebrates. Lineage-specific and even species-specific expansion of HERC7 subfamily in fish indicates that crucian carp HERC7 might be species-specific. In virally infected fish cells, HERC7 is induced by IFN and selectively targets three retinoic acid-inducible gene-I-like receptor signaling factors for degradation to attenuate IFN response by two distinct strategies. Mechanistically, HERC7 delivers mediator of IFN regulatory factor 3 activator and mitochondrial antiviral signaling protein for proteasome-dependent degradation at the protein level and facilitates IFN regulatory factor 7 transcript decay at the mRNA level, thus abrogating cellular IFN induction to promote virus replication. Whereas HERC7 is a putative E3 ligase, the E3 ligase activity is not required for its negative regulatory function. These results demonstrate that the ongoing expansion of the small HERC family generates a novel HERC7 to fine-tune fish IFN antiviral response.
小型 HERC 家族目前由四个成员（HERC3-6）组成，参与多种生理活动的调节。HERCs 在 IFN 反应中的作用知之甚少。在这项研究中，我们鉴定了一种新型鱼类 HERC 成员，命名为鲫鱼 HERC7，作为鱼类 IFN 反应的负调控因子。同源物的全基因组搜索和综合系统发育分析表明，小型 HERC 家族除了在哺乳动物中得到充分研究的 HERC3-6 之外，还包含一个仅存在于非哺乳动物脊椎动物中的新型 HERC7 亚家族。HERC7 亚家族在鱼类中的谱系特异性甚至种特异性扩张表明，鲫鱼 HERC7 可能是种特异性的。在病毒感染的鱼类细胞中，IFN 诱导 HERC7 的表达，并通过两种不同的策略选择性地靶向三种视黄酸诱导基因-I 样受体信号因子进行降解，从而减弱 IFN 反应。在机制上，HERC7 在蛋白质水平上促进干扰素调节因子 3 激活物和线粒体抗病毒信号蛋白向蛋白酶体依赖性降解的传递，并促进 IFN 调节因子 7 转录物的衰减，从而阻断细胞 IFN 的诱导以促进病毒复制。虽然 HERC7 是一种假定的 E3 连接酶，但 E3 连接酶活性不是其负调节功能所必需的。这些结果表明，小型 HERC 家族的持续扩张产生了一种新型的 HERC7，以微调鱼类的 IFN 抗病毒反应。
