Acetylation licenses Th1 cell polarization to constrain Listeria monocytogenes infection
Acetylation licenses Th1 cell polarization to constrain Listeria monocytogenes infection
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DOI：
10.1038/s41418-022-01017-9
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发表时间：
2022-05
影响因子：
12.4
通讯作者：
Yanan S Zhang;Dazhuan E Xin;Zhizhang Wang;Wenzhe Peng;Yuanyuan Zeng;Jia-Long Liang;Mengmeng Xu
中科院分区：
文献类型：
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作者：
Yanan S Zhang;Dazhuan E Xin;Zhizhang Wang;Wenzhe Peng;Yuanyuan Zeng;Jia-Long Liang;Mengmeng Xu
辅助性T细胞1（Th 1）免疫通常被视为脊椎动物对抗细胞内病原体的关键适应。识别新的靶点以增强Th 1细胞分化和功能对于抗感染免疫越来越重要。在这里，通过在体外Th 1细胞分化过程中关注表观遗传修饰剂的小分子筛选，我们确定了选择性组蛋白脱乙酰酶6（HDAC 6）抑制剂ricolinostat和nexturastat A（Nex A）促进Th 1细胞分化。HDAC 6缺失的小鼠表现出Th 1细胞分化的提高，单核细胞增生李斯特菌感染的严重程度降低。在机制上，HDAC 6通过其酶活性直接脱乙酰化CBP催化的信号转导子和转录激活因子4（STAT 4）-赖氨酸（K）667的乙酰化。STAT 4-K667的乙酰化是JAK 2介导的STAT 4磷酸化和活化所必需的。我们的研究确定了STAT 4-K667的乙酰化是Th 1细胞分化和防御细胞内病原体感染的重要信号事件，并强调了HDAC 6抑制剂控制细胞内病原体感染的治疗潜力。
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 ofListeria monocytogenesinfection. 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.Stat4K667Rmutant mice lost the ability to normally differentiate into Th1 cells and developed severeListeriainfection. 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.