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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antiviral Agents / metabolism*
-
Cell Line
-
Chromones / pharmacology
-
DNA-Activated Protein Kinase / antagonists & inhibitors
-
DNA-Activated Protein Kinase / deficiency*
-
DNA-Activated Protein Kinase / metabolism
-
Female
-
Fibroblasts / drug effects
-
Fibroblasts / metabolism
-
Humans
-
Immunity, Innate*
-
Male
-
Mice, Inbred C57BL
-
Morpholines / pharmacology
-
Nucleotidyltransferases / metabolism*
-
Phosphorylation / drug effects
-
Protein Kinase Inhibitors / pharmacology
-
Protein Multimerization / drug effects
-
Signal Transduction / drug effects
-
Simplexvirus / drug effects
-
Simplexvirus / physiology
-
THP-1 Cells
-
Vesiculovirus / drug effects
-
Vesiculovirus / physiology
-
Virus Replication / drug effects
Substances
-
8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one
-
Antiviral Agents
-
Chromones
-
Morpholines
-
Protein Kinase Inhibitors
-
DNA-Activated Protein Kinase
-
Nucleotidyltransferases
-
cGAS protein, human
-
cGAS protein, mouse