DNA-PK deficiency potentiates cGAS-mediated antiviral innate immunity
| Autor: | Alexandre Belot, Yu Guo, Pinghui Feng, Jun Xie, Hong-Bing Shu, Hansong Xia, Jun Zhao, Li Zhong, Junjie Zhang, Qing Yang, Ting Liu, Mi Li, Xiaona Sun, Isabelle Rouvet, Cheng Peng |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine THP-1 Cells Morpholines Protein subunit Science General Physics and Astronomy DNA-Activated Protein Kinase Biology Virus Replication medicine.disease_cause Antiviral Agents Article General Biochemistry Genetics and Molecular Biology Cell Line Autoimmunity 03 medical and health sciences 0302 clinical medicine Immune system Virology medicine Animals Humans Simplexvirus Missense mutation Phosphorylation Protein kinase A Protein Kinase Inhibitors Innate immunity Multidisciplinary Innate immune system Vesiculovirus General Chemistry Fibroblasts Nucleotidyltransferases Immunity Innate Mice Inbred C57BL 030104 developmental biology Viral replication Chromones Cancer research Female Protein Multimerization 030217 neurology & neurosurgery RNA Guide Kinetoplastida Signal Transduction |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-15 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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