KAT8 selectively inhibits antiviral immunity by acetylating IRF3.

Abstract

The transcription factor interferon regulatory factor 3 (IRF3) is essential for virus infection-triggered induction of type I interferons (IFN-I) and innate immune responses. IRF3 activity is tightly regulated by conventional posttranslational modifications (PTMs) such as phosphorylation and ubiquitination. Here, we identify an unconventional PTM of IRF3 that directly inhibits its transcriptional activity and attenuates antiviral immune response. We performed an RNA interference screen and found that lysine acetyltransferase 8 (KAT8), which is ubiquitously expressed in immune cells (particularly in macrophages), selectively inhibits RNA and DNA virus-triggered IFN-I production in macrophages and dendritic cells. KAT8 deficiency protects mice from viral challenge by enhancing IFN-I production. Mechanistically, KAT8 directly interacts with IRF3 and mediates IRF3 acetylation at lysine 359 via its MYST domain. KAT8 inhibits IRF3 recruitment to IFN-I gene promoters and decreases the transcriptional activity of IRF3. Our study reveals a critical role for KAT8 and IRF3 lysine acetylation in the suppression of antiviral innate immunity.

• Authors: Wanwan Huai, Xingguang Liu, Chunmei Wang, Yunkai Zhang, Xi Chen, Xiang Chen, Sheng Xu, Tim Thomas, Nan Li, Xuetao Cao
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 216 Issue 4 Pg. 772-785 (04 01 2019) ISSN: 1540-9538 [Electronic] United States
• PMID: 30842237 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Huai et al.

Chemical References

• IRF3 protein, human
• Interferon Regulatory Factor-3
• Interferon Type I
• Irf3 protein, mouse
• Histone Acetyltransferases
• KAT8 protein, human
• Kat8 protein, mouse

Topics

• Acetylation
• Animals
• Dendritic Cells (metabolism, virology)
• Female
• HEK293 Cells
• Histone Acetyltransferases (genetics, metabolism)
• Humans
• Immunity, Innate (immunology)
• Interferon Regulatory Factor-3 (genetics, metabolism)
• Interferon Type I (metabolism)
• Macrophages (metabolism, virology)
• Male
• Mice
• Mice, Inbred C57BL
• RAW 264.7 Cells
• RNA Interference
• Transcriptional Activation
• Transfection
• Vesicular Stomatitis (immunology, virology)
• Vesicular stomatitis Indiana virus (immunology)