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. 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.
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Data availability
RNA-seq datasets are deposited in the Gene Expression Omnibus (GEO) with accession number GEO: GSE146253. We collected ChIP-seq and ATAC-seq data from the GEO public resource (http://www.ncbi.nlm.nih.gov/geo) and the accession numbers are GSM550303, GSM550304, GSM2828376, GSM2828377, GSM2828378, GSM2828379, GSM836118, GSM836120, GSM994512, and GSM994513. All of the full length original western blots for these results are provide in Supplementary File 1.
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Acknowledgements
We are grateful to Yu Zhang for providing us with the Hdac6–/– mice. Jingjing Wang and Qi Li for technical help in L. monocytogenes infection experiments. We are grateful to Bing Su for manuscript review and discussion.
Funding
YZ was supported by the Young Scientists Fund of the National Natural Science Foundation Grant of China (32000620). This work was supported by National Natural Science Foundation Grant of China (81820108023, U1603284 and 81530083), Young Scientists Fund of the National Natural Science Foundation Grant of China (31700789), National Key Research and Development Program of China (2016YFC1302402), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).
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YZ and DX contributed to the experimental design, conductions of experiments, and manuscript preparation. ZW and WP performed the experiments, data analysis and manuscript preparation. YZ, JL, MX, NC, JZ, YJ, MC and YW assisted with the experiments. MC and JY provided technical assistance. ZC, XL and LC contributed to the data analysis and manuscript writing. YC was involved in the conception of the research, experimental design, data analysis, and manuscript preparation.
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All animal experiments were performed in compliance with the guide for the care and use of laboratory animals and were approved by the institutional biomedical research ethics committee of Soochow University.
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Zhang, Y.S., Xin, D.E., Wang, Z. et al. Acetylation licenses Th1 cell polarization to constrain Listeria monocytogenes infection. Cell Death Differ 29, 2303–2315 (2022). https://doi.org/10.1038/s41418-022-01017-9
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DOI: https://doi.org/10.1038/s41418-022-01017-9
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