Acetylation licenses Th1 cell polarization to constrain Listeria monocytogenes infection.

Cell death and differentiation 2022 Nov

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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. © 2022. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.

Citation

Yanan Sophia Zhang, Dazhuan Eric Xin, Zhizhang Wang, Wenlong Peng, Yuanyuan Zeng, Jianshu Liang, Mengmeng Xu, Nannan Chen, Jie Zhang, Jicheng Yue, Mengtao Cao, Chenxi Zhang, Yuting Wang, Zhijie Chang, Xiao-Mei Lu, Lei Chang, Y Eugene Chinn. Acetylation licenses Th1 cell polarization to constrain Listeria monocytogenes infection. Cell death and differentiation. 2022 Nov;29(11):2303-2315