The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, State Key Laboratory of Virology, Wuhan University, Wuhan, China.
Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
Nat Commun. 2020 Dec 3;11(1):6182. doi: 10.1038/s41467-020-19941-0.
Upon sensing cytosolic DNA, the enzyme cGAS induces innate immune responses that underpin anti-microbial defenses and certain autoimmune diseases. Missense mutations of PRKDC encoding the DNA-dependent protein kinase (DNA-PK) catalytic subunit (DNA-PKcs) are associated with autoimmune diseases, yet how DNA-PK deficiency leads to increased immune responses remains poorly understood. In this study, we report that DNA-PK phosphorylates cGAS and suppresses its enzymatic activity. DNA-PK deficiency reduces cGAS phosphorylation and promotes antiviral innate immune responses, thereby potently restricting viral replication. Moreover, cells isolated from DNA-PKcs-deficient mice or patients carrying PRKDC missense mutations exhibit an inflammatory gene expression signature. This study provides a rational explanation for the autoimmunity of patients with missense mutations of PRKDC, and suggests that cGAS-mediated immune signaling is a potential target for therapeutic interventions.
当感知到细胞质 DNA 时，酶 cGAS 会引发先天免疫反应，为抗微生物防御和某些自身免疫性疾病提供支撑。编码 DNA 依赖性蛋白激酶（DNA-PK）催化亚基（DNA-PKcs）的 PRKDC 错义突变与自身免疫性疾病相关，但 DNA-PK 缺乏如何导致免疫反应增加仍知之甚少。在这项研究中，我们报告称，DNA-PK 可使 cGAS 磷酸化并抑制其酶活性。DNA-PK 缺乏会降低 cGAS 的磷酸化水平，并促进抗病毒的先天免疫反应，从而有效地抑制病毒复制。此外，从 DNA-PKcs 缺陷型小鼠或携带 PRKDC 错义突变的患者中分离出的细胞表现出炎症基因表达特征。这项研究为 PRKDC 错义突变患者的自身免疫现象提供了合理的解释，并表明 cGAS 介导的免疫信号是治疗干预的潜在靶点。
