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.

Abstract

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.

原文链接见：

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712783/