Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-020-19941-0
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Funding
- Wuhan University
- National Natural Science Foundation of China [31970156]
- Fundamental Research Funds for the Central Universities [2042019kf0202]
- NIH [R35DE027556, R01DE026003, R01CA221521, R21AI134105]
- NCI [CA221521]
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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. The enzyme cGAS induces innate immune responses upon recognition of cytosolic DNA. Here, using in vitro and in vivo models, the authors identify DNA-PK as a negative regulator of cGAS signalling.
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