Downregulation of host gene expression is a key strategy employed by intracellular pathogens for their survival in macrophages and subsequent pathogenesis. In a previous study, we have shown that histone deacetylase 1 (HDAC1) levels go up in macrophages infected with Mycobacterium tuberculosis, and it hypoacetylates histone H3 at the promoter of IL-12B gene, leading to its downregulation. We now show that after infection with M. tuberculosis, HDAC1 is phosphorylated, and the levels of phosphorylated HDAC1 (pHDAC1) increase significantly in macrophages. We found that transcriptional repressor protein zinc finger and BTB domain 25 (ZBTB25) and transcriptional corepressor Sin3a associate with the HDAC1 silencing complex, which is recruited to the promoter of IL-12B to downregulate its expression in infected macrophages. Knocking down of ZBTB25 enhanced release of IL-12p40 from infected macrophages. Inhibition of HDAC1 and ZBTB25 promoted colocalization of M. tuberculosis and LC3 (microtubule-associated protein 1A/1B-light chain 3) in autophagosomes. Induction of autophagy resulted in the killing of intracellular M. tuberculosis. Enhanced phosphorylation of JAK2 and STAT4 was observed in macrophages upon treatment with HDAC1 and ZBTB inhibitors, and inhibition of JAK2/STAT4 negated the killing of the intracellular pathogen, suggesting their role in the autophagy-mediated killing of intracellular M. tuberculosis. In view of the emergence of drug resistance in M. tuberculosis, host-directed therapy is an attractive alternative strategy to combat tuberculosis (TB). HDACs have been proposed to be host targets for TB treatment. Our study indicates that ZBTB25, a functional subunit of the HDAC1/Sin3a repressor complex involved in IL-12B suppression, could be an alternative target for host-directed anti-TB therapy.

中文翻译：

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转录抑制蛋白 ZBTB25 与结核分枝杆菌感染巨噬细胞中的 HDAC1-Sin3a 复合物相关联，其抑制作用可通过自噬清除病原体

宿主基因表达的下调是细胞内病原体在巨噬细胞中存活和随后的发病机制所采用的关键策略。在之前的一项研究中，我们已经表明组蛋白去乙酰化酶 1 (HDAC1) 水平在感染结核分枝杆菌的巨噬细胞中升高，并且它使IL-12B基因启动子处的组蛋白 H3 低乙酰化，导致其下调。我们现在表明，感染结核分枝杆菌后，HDAC1 被磷酸化，巨噬细胞中磷酸化 HDAC1 (pHDAC1) 的水平显着增加。我们发现转录抑制蛋白锌指和 BTB 结构域 25 (ZBTB25) 以及转录辅助抑制蛋白 Sin3a 与 HDAC1 沉默复合物相关，后者被募集到IL-12B下调其在感染巨噬细胞中的表达。敲低ZBTB25 可增强受感染巨噬细胞中 IL-12p40 的释放。HDAC1 和 ZBTB25 的抑制促进了结核分枝杆菌和 LC3（微管相关蛋白 1A/ 1B-轻链 3）在自噬体中的共定位。自噬的诱导导致细胞内结核分枝杆菌的杀死。在用 HDAC1 和 ZBTB 抑制剂处理后，巨噬细胞中观察到 JAK2 和 STAT4 的磷酸化增强，并且 JAK2/STAT4 的抑制抵消了细胞内病原体的杀伤，表明它们在自噬介导的细胞内结核分枝杆菌杀伤中的作用。鉴于耐药性的出现结核分枝杆菌，宿主导向疗法是对抗结核病 (TB) 的一种有吸引力的替代策略。HDAC 已被提议作为结核病治疗的宿主目标。我们的研究表明，ZBTB25 是参与IL-12B抑制的 HDAC1/Sin3a 抑制复合物的功能亚基，可能是宿主定向抗结核治疗的替代靶点。