Histone deacetylase 3 contributes to the antiviral innate immunity of macrophages by interacting with FOXK1 to regulate STAT1/2 transcription

Liping Yang; Shengchuan Chen; Qun Zhao; Chaohu Pan; Linan Peng; Yu Han; Lili Li; Jiayin Ruan; Jingyan Xia; Heng Yang; Feng Xu; Genhong Cheng

doi:10.1016/j.celrep.2022.110302

Histone deacetylase 3 contributes to the antiviral innate immunity of macrophages by interacting with FOXK1 to regulate STAT1/2 transcription

Cell Rep. 2022 Jan 25;38(4):110302. doi: 10.1016/j.celrep.2022.110302.

Authors

Liping Yang¹, Shengchuan Chen², Qun Zhao³, Chaohu Pan⁴, Linan Peng⁵, Yu Han¹, Lili Li⁴, Jiayin Ruan⁴, Jingyan Xia⁶, Heng Yang⁷, Feng Xu⁸, Genhong Cheng⁹

Affiliations

¹ Department of Infectious Diseases, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, China.
² Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, China; Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
³ CAS Key Laboratory of Separation Sciences for Analytical Chemistry, National Chromatographic R&A Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning 116023, China.
⁴ Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, China.
⁵ School of Medicine, Xiamen University, Xiamen 361000, China.
⁶ Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
⁷ Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, China. Electronic address: yhmyt@hotmail.com.
⁸ Department of Infectious Diseases, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China. Electronic address: xufeng99@zju.edu.cn.
⁹ Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: gcheng@mednet.ucla.edu.

PMID: 35081346
DOI: 10.1016/j.celrep.2022.110302

Abstract

It is well known that interferon (IFN)-α/-β activates the JAK/STAT signaling pathway and suppresses viral replication through the induction of IFN stimulated genes (ISGs). Here, we report that knockout of HDAC3 from macrophages results in the decreased expression of STAT1 and STAT2, leading to defective antiviral immunity in cells and mice. Further studies show that HDAC3 interacts with a conserved transcription factor Forkhead Box K1 (FOXK1), co-localizes with FOXK1 at the promoter of STAT1 and STAT2, and is required for protecting FOXK1 from lysosomal system-mediated degradation. FOXK1-deficient macrophages also show low STAT1 and STAT2 expression with defective responses to viruses. Thus, our studies uncover the biological importance of HDAC3 in regulating the antiviral immunity of macrophages through interacting with FOXK1 to regulate the expression of STAT1 and STAT2.

Keywords: FOXK1; HDAC3; STAT1; STAT2; transcription regulation; type I interferon.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Forkhead Transcription Factors / immunology
Gene Expression Regulation / immunology*
Histone Deacetylases / immunology*
Immunity, Innate / immunology*
Macrophages / immunology*
Mice
STAT1 Transcription Factor / biosynthesis
STAT1 Transcription Factor / immunology
STAT2 Transcription Factor / biosynthesis
STAT2 Transcription Factor / immunology
Transcription, Genetic
Virus Diseases / immunology*

Substances

Forkhead Transcription Factors
Foxk1 protein, mouse
STAT1 Transcription Factor
STAT2 Transcription Factor
Histone Deacetylases
histone deacetylase 3