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.
- 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.
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. Stat4K667R 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.