DNA-PK deficiency potentiates cGAS-mediated antiviral innate immunity

  • Nat Commun. 2020 Dec 3;11(1):6182. doi: 10.1038/s41467-020-19941-0.
Xiaona Sun  1  2 ,  Ting Liu  1  2 ,  Jun Zhao  3 ,  Hansong Xia  3  4 ,  Jun Xie  1  2 ,  Yu Guo  1  2 ,  Li Zhong  2 ,  Mi Li  2 ,  Qing Yang  2 ,  Cheng Peng  5 ,  Isabelle Rouvet  6 ,  Alexandre Belot  7  8  9 ,  Hong-Bing Shu  2 ,  Pinghui Feng  10 ,  Junjie Zhang  11  12
Affiliations
  • 1. The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, State Key Laboratory of Virology, Wuhan University, Wuhan, China.
  • 2. Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
  • 3. Section of Infection and Immunity, Herman Ostrow School of Dentistry, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
  • 4. Department of Orthopaedics, 3rd Xiangya Hospital, Central South University, Changsha, China.
  • 5. Department of Burns and Plastic Surgery, 3rd Xiangya Hospital, Central South University, Changsha, China.
  • 6. Hospices Civils de Lyon, Centre de Biotechnologie Cellulaire et Biothèque, Bron, France.
  • 7. Centre International de Recherche en Infectiologie, CIRI, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, University of Lyon, Lyon, France.
  • 8. National Referee Centre for Pediatric-Onset Rheumatism and Autoimmune Diseases (RAISE), Lyon, France.
  • 9. Hospices Civils de Lyon, Paediatric Nephrology, Rheumatology, Dermatology Unit, Mother and Children University Hospital, Bron, France.
  • 10. Section of Infection and Immunity, Herman Ostrow School of Dentistry, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA. [email protected].
  • 11. The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, State Key Laboratory of Virology, Wuhan University, Wuhan, China. [email protected].
  • 12. Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China. [email protected].
PMID: 33273464 DOI: 10.1038/s41467-020-19941-0
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.

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