DNA-PK deficiency potentiates cGAS-mediated antiviral innate immunity

Xiaona Sun, Ting Liu, Jun Zhao, Hansong Xia, Jun Xie, Yu Guo, Li Zhong, Mi Li, Qing Yang, Cheng Peng, Isabelle Rouvet, Alexandre Belot, Hong-Bing Shu, Pinghui Feng () and Junjie Zhang ()
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Xiaona Sun: Wuhan University
Ting Liu: Wuhan University
Jun Zhao: University of Southern California
Hansong Xia: University of Southern California
Jun Xie: Wuhan University
Yu Guo: Wuhan University
Li Zhong: Wuhan University
Mi Li: Wuhan University
Qing Yang: Wuhan University
Cheng Peng: Central South University
Isabelle Rouvet: Centre de Biotechnologie Cellulaire et Biothèque
Alexandre Belot: Centre International de Recherche en Infectiologie, CIRI, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, University of Lyon
Hong-Bing Shu: Wuhan University
Pinghui Feng: University of Southern California
Junjie Zhang: Wuhan University

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19941-0

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