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

• Published in: Cell reports (Cambridge) Vol. 38; no. 4; p. 110302
• Main Authors: Yang, Liping, Chen, Shengchuan, Zhao, Qun, Pan, Chaohu, Peng, Linan, Han, Yu, Li, Lili, Ruan, Jiayin, Xia, Jingyan, Yang, Heng, Xu, Feng, Cheng, Genhong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.01.2022; Elsevier
• Subjects: Animals; Forkhead Transcription Factors - immunology; FOXK1; Gene Expression Regulation - immunology; HDAC3; Histone Deacetylases - immunology; Immunity, Innate - immunology; Macrophages - immunology; Mice; STAT1; STAT1 Transcription Factor - biosynthesis; STAT1 Transcription Factor - immunology; STAT2; STAT2 Transcription Factor - biosynthesis; STAT2 Transcription Factor - immunology; transcription regulation; Transcription, Genetic; type I interferon; Virus Diseases - immunology; type I interferon; transcription regulation; FOXK1; HDAC3; STAT1; STAT2
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110302

[Display omitted] 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. •HDAC3 deficiency impairs the antiviral immunity of macrophages in vivo and in vitro•HDAC3 interacts with FOXK1 and co-localizes at the promoters of STAT1 and STAT2•HDAC3 and FOXK1 positively regulate the expression of STAT1/2 and downstream ISGs•HDAC3 is required for preventing FOXK1 from lysosomal degradation Yang et al. show that HDAC3 and FOXK1 form a transcriptional complex to positively regulate STAT1/2 expression, which is required for the cascade activation of type I interferon response. Lysosomal degradation of FOXK1, reduction of type I interferon response, and impaired antiviral immunity are observed in HDAC3 knockout macrophages.