KAT5 acetylates cGAS to promote innate immune response to DNA virus.

Ze-Min Song, Heng Lin, Xue-Mei Yi, Wei Guo, Ming-Ming Hu, Hong-Bing Shu

Proceedings of the National Academy of Sciences of the United States of America 2020 Sep 01

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The DNA sensor cGMP-AMP synthase (cGAS) senses cytosolic microbial or self DNA to initiate a MITA/STING-dependent innate immune response. cGAS is regulated by various posttranslational modifications at its C-terminal catalytic domain. Whether and how its N-terminal unstructured domain is regulated by posttranslational modifications remain unknown. We identified the acetyltransferase KAT5 as a positive regulator of cGAS-mediated innate immune signaling. Overexpression of KAT5 potentiated viral-DNA-triggered transcription of downstream antiviral genes, whereas a KAT5 deficiency had the opposite effects. Mice with inactivated Kat5 exhibited lower levels of serum cytokines in response to DNA virus infection, higher viral titers in the brains, and more susceptibility to DNA-virus-induced death. Mechanistically, KAT5 catalyzed acetylation of cGAS at multiple lysine residues in its N-terminal domain, which promoted its DNA-binding ability. Our findings suggest that KAT5-mediated cGAS acetylation at its N terminus is important for efficient innate immune response to DNA virus.

Citation

Ze-Min Song, Heng Lin, Xue-Mei Yi, Wei Guo, Ming-Ming Hu, Hong-Bing Shu. KAT5 acetylates cGAS to promote innate immune response to DNA virus. Proceedings of the National Academy of Sciences of the United States of America. 2020 Sep 01;117(35):21568-21575