Acetylation licenses Th1 cell polarization to constrain Listeria monocytogenes infection

Cell Death Differ. 2022 Nov;29(11):2303-2315. doi: 10.1038/s41418-022-01017-9.

Yanan Sophia Zhang ^# ¹ ², Dazhuan Eric Xin ^# ³, Zhizhang Wang ^# ⁴, Wenlong Peng ², Yuanyuan Zeng ⁵, Jianshu Liang ², Mengmeng Xu ² ⁶, Nannan Chen ², Jie Zhang ², Jicheng Yue ², Mengtao Cao ⁷, Chenxi Zhang ³, Yuting Wang ², Zhijie Chang ⁸, Xiao-Mei Lu ⁹, Lei Chang ², Y Eugene Chinn ¹⁰ ¹¹

Affiliations

1 Institue of Clinical Medicine, Zhejiang Provincial People's Hospital of Hangzhou Medical College, 158 Shangtang Road, Hangzhou, Zhejiang, 310000, China.
2 Institutes of Biology and Medical Sciences, School of Radiation Medicine and Protection School of Radiological and Interdisciplinary Science, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu, 215123, China.
3 Institue of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.
4 Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
5 Department of Respiratory Medicine, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China.
6 Department of Pathology, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215000, China.
7 Department of Respiratory and Critical Care Medicine, Shenzhen Longhua District Central Hospital, Guangdong Medical University Affiliated Longhua District Central Hospital, Shenzhen, 518300, China.
8 State Key Laboratory of Membrane Biology, Tsinghua University School of Medicine, 100084, Beijing, China.
9 Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi, 830011, China.
10 Institue of Clinical Medicine, Zhejiang Provincial People's Hospital of Hangzhou Medical College, 158 Shangtang Road, Hangzhou, Zhejiang, 310000, China. [email protected].
11 Institutes of Biology and Medical Sciences, School of Radiation Medicine and Protection School of Radiological and Interdisciplinary Science, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu, 215123, China. [email protected].
# Contributed equally.

PMID: 35614130 DOI: 10.1038/s41418-022-01017-9

Abstract

T helper 1 (Th1) immunity is typically viewed as a critical adaptation by vertebrates against intracellular pathogens. Identifying novel targets to enhance Th1 cell differentiation and function is increasingly important for Anti-infection immunity. Here, through small-molecule screening focusing on epigenetic modifiers during the in vitro Th1 cell differentiation process, we identified that the selective histone deacetylase 6 (HDAC6) inhibitors ricolinostat and nexturastat A (Nex A) promoted Th1 cell differentiation. HDAC6-depleted mice exhibit elevation of Th1 cell differentiation, and decreased severity of Listeria monocytogenes Infection. Mechanistically, HDAC6 directly deacetylated CBP-catalyzed acetylation of signal transducer and activator of transcription 4 (STAT4)-lysine (K) 667 via its enzymatic activity. Acetylation of STAT4-K667 is required for JAK2-mediated phosphorylation and activation of STAT4. Stat4^K667R mutant mice lost the ability to normally differentiate into Th1 cells and developed severe Listeria Infection. Our study identifies acetylation of STAT4-K667 as an essential signaling event for Th1 cell differentiation and defense against intracellular pathogen infections, and highlights the therapeutic potential of HDAC6 inhibitors for controlling intracellular pathogen infections.

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