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

Xiaona SunTing LiuJun ZhaoHansong XiaJun XieYu GuoLi ZhongMi LiQing YangCheng PengIsabelle RouvetAlexandre BelotHong-Bing ShuPinghui FengJunjie Zhang
Published in: Nature communications (2020)
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.
Keyphrases
  • circulating tumor
  • immune response
  • cell free
  • single molecule
  • gene expression
  • nucleic acid
  • dna methylation
  • sars cov
  • risk assessment
  • inflammatory response
  • patient reported