CD82 hypomethylation is essential for tuberculosis pathogenesis via regulation of RUNX1-Rab5/22.
CD82 hypomethylation is essential for tuberculosis pathogenesis via regulation of RUNX1-Rab5/22.
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DOI：
10.1038/s12276-018-0091-4
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发表时间：
2018-05-14
影响因子：
12.8
通讯作者：
Yang CS
中科院分区：
文献类型：
--
作者：
Koh HJ;Kim YR;Kim JS;Yun JS;Kim S;Kim SY;Jang K;Yang CS
肿瘤抑制基因CD82/KAI1是四跨膜蛋白超家族的成员，并组织各种基于膜的过程。结核分枝杆菌（MTB）通过干扰吞噬溶酶体生物合成和炎症反应而在宿主巨噬细胞中持续存在，但CD82在控制巨噬细胞内致病分枝杆菌细胞内存活中的作用仍知之甚少。在这项研究中，我们证明了毒性MTB菌株H37 Rv（MTB Rv）诱导CD82启动子低甲基化，导致CD82表达。通过与Rab5/22相互作用，CD82靶向Runt相关转录因子1（RUNX1）对于吞噬体停滞是必需的。这种阻滞是MTB在体外和体内的细胞内生长所需的，但不是MTB H37Ra（MTB Ra）在巨噬细胞中的细胞内生长所需的。此外，CD82或RUNX1的敲低或敲除通过吞噬溶酶体生物发生、炎性细胞因子产生和随后的体外和体内抗微生物活性增加了抗细菌宿主防御。值得注意的是，结核病（TB）患者肉芽肿中CD82和RUNX1的水平升高，表明CD82和RUNX1在人类TB中具有临床意义。我们的研究结果确定了一个以前未被认识到的作用，CD82低甲基化的调节吞噬体成熟，增强细胞内生存，和先天性宿主免疫反应结核分枝杆菌。因此，CD82-RUNX1-Rab5/22轴可能是以前未认识到的MTB致病的毒力机制。结核病致病菌结核分枝杆菌调节肿瘤抑制基因，以便在宿主免疫细胞中存活和生长。韩国汉阳大学的Chul-Su Yang及其同事发现，这种细菌可以通过从其DNA序列中去除甲基来刺激巨噬细胞中CD82的表达。CD82的低甲基化区域与蛋白质相互作用并激活这些蛋白质，这些蛋白质干扰细胞产生炎症反应的能力，并降解称为溶酶体的专门胞内囊泡中的细菌。CD82缺陷小鼠感染结核后存活率的增加以及在结核病患者炎性病变中发现的CD82蛋白水平的升高进一步支持了该蛋白在M.肺结核感染。靶向CD82介导的信号传导可能是设计新疗法的有前途的方法。
The tumor suppressor gene CD82/KAI1 is a member of the tetraspanin superfamily and organizes various membrane-based processes. Mycobacterium tuberculosis (MTB) persists in host macrophages by interfering with phagolysosome biogenesis and inflammatory responses, but the role of CD82 in controlling the intracellular survival of pathogenic mycobacteria within macrophages remains poorly understood. In this study, we demonstrated that the virulent MTB strain H37Rv (MTB Rv) induced CD82 promoter hypomethylation, resulting in CD82 expression. Targeting of the runt-related transcription factor 1 (RUNX1) by CD82 is essential for phagosome arrest via interacting with Rab5/22. This arrest is required for the intracellular growth of MTB in vitro and in vivo, but not for that of MTB H37Ra (MTB Ra) in macrophages. In addition, knockdown or knockout of CD82 or RUNX1 increased antibacterial host defense via phagolysosome biogenesis, inflammatory cytokine production, and subsequent antimicrobial activity both in vitro and in vivo. Notably, the levels of CD82 and RUNX1 in granulomas were elevated in tuberculosis (TB) patients, indicating that CD82 and RUNX1 have clinical significance in human TB. Our findings identify a previously unrecognized role of CD82 hypomethylation in the regulation of phagosome maturation, enhanced intracellular survival, and the innate host immune response to MTB. Thus, the CD82–RUNX1–Rab5/22 axis may be a previously unrecognized virulence mechanism of MTB pathogenesis. The tuberculosis-causing bacterium Mycobacterium tuberculosis regulates a tumor suppressor gene in order to survive and grow in host immune cells. Chul-Su Yang and colleagues at Hanyang University, South Korea, have found that the bacterium can stimulate the expression of CD82 in macrophages by removing methyl groups from its DNA sequence. CD82’s hypomethylated region interacts with and activates proteins that interfere with the cell’s ability to mount an inflammatory response and degrade bacteria in specialized intracellular vesicles called lysosomes. The increased survival rate of CD82-deficient mice following infection with tuberculosis and the elevated levels of CD82 protein found in the inflammatory lesions of patients with tuberculosis further support a previously unrecognized role for this protein in M. tuberculosis infection. Targeting CD82-mediated signaling could be a promising approach for designing new therapeutics.
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