20201203 DNA-PK deficiency potentiates cGAS-mediated antiviral innate immunity

Sun, X., Liu, T., Zhao, J., Xia, H., Xie, J., Guo, Y., Zhong, L., Li, M., Yang, Q., Peng, C., Rouvet, I., Belot, A., Shu, H. B., Feng, P.*, Zhang, J.* (2020). DNA-PK deficiency potentiates cGAS-mediated antiviral innate immunity. Nat Commun 11, 6182.


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.




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