Autophagy receptor CCDC50 tunes the STING-mediated interferon response in viral infections and autoimmune diseases
Autophagy receptor CCDC50 tunes the STING-mediated interferon response in viral infections and autoimmune diseases
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自噬受体 CCDC50 调节病毒感染和自身免疫性疾病中 STING 介导的干扰素反应
DOI：
10.1038/s41423-021-00758-w
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发表时间：
2021-08-27
影响因子：
24.1
通讯作者：
Guo, Deyin
中科院分区：
文献类型：
--
作者：
Hou, Panpan;Lin, Yuxin;Guo, Deyin
DNA传感和干扰素（IFN）介导的先天免疫的及时激活对于防御DNA病毒感染和清除异常细胞至关重要。然而，免疫反应的过度激活可能导致组织损伤和自身免疫性疾病;因此，这些过程必须受到复杂的调节。STING是关键的衔接蛋白，其被环GMP-AMP激活，环GMP-AMP是来自cGAS介导的DNA传感的第二信使。在这里，我们报告说，CCDC 50，一个新发现的自噬受体，调谐STING定向的I型IFN信号传导活性，通过提供K63-polyubiquitinated STING到autolysosomes降解。Ccdc 50基因敲除可显著增加单纯疱疹病毒1型（HSV-1）或DNA配体诱导的I型IFN和促炎细胞因子的产生。Ccdc 50基因敲除的小鼠与其野生型同窝小鼠相比，在HSV-1攻击下，IFN产生增加，病毒复制减少，细胞浸润减少，存活率提高。值得注意的是，CCDC 50的表达在系统性红斑狼疮（SLE）（一种慢性自身免疫性疾病）中下调。CCDC 50水平与IFN信号通路激活和SLE患者疾病严重程度呈负相关。CCDC 50缺陷增强cGAS-STING介导的由SLE血清触发的免疫应答。因此，我们的研究结果揭示了CCDC 50在病毒感染和自身免疫性疾病的免疫调节中的关键作用，并为CCDC 50操纵的治疗意义提供了见解。
DNA sensing and timely activation of interferon (IFN)-mediated innate immunity are crucial for the defense against DNA virus infections and the clearance of abnormal cells. However, overactivation of immune responses may lead to tissue damage and autoimmune diseases; therefore, these processes must be intricately regulated. STING is the key adaptor protein, which is activated by cyclic GMP-AMP, the second messenger derived from cGAS-mediated DNA sensing. Here, we report that CCDC50, a newly identified autophagy receptor, tunes STING-directed type I IFN signaling activity by delivering K63-polyubiquitinated STING to autolysosomes for degradation. Knockout of CCDC50 significantly increases herpes simplex virus 1 (HSV-1)- or DNA ligand-induced production of type I IFN and proinflammatory cytokines.Ccdc50-deficient mice show increased production of IFN, decreased viral replication, reduced cell infiltration, and improved survival rates compared with their wild-type littermates when challenged with HSV-1. Remarkably, the expression of CCDC50 is downregulated in systemic lupus erythematosus (SLE), a chronic autoimmune disease. CCDC50 levels are negatively correlated with IFN signaling pathway activation and disease severity in human SLE patients. CCDC50 deficiency potentiates the cGAS-STING-mediated immune response triggered by SLE serum. Thus, our findings reveal the critical role of CCDC50 in the immune regulation of viral infections and autoimmune diseases and provide insights into the therapeutic implications of CCDC50 manipulation.