Mycobacterium tuberculosis ESX-1-secreted substrate protein EspC promotes mycobacterial survival through endoplasmic reticulum stress-mediated apoptosis.
Mycobacterium tuberculosis ESX-1-secreted substrate protein EspC promotes mycobacterial survival through endoplasmic reticulum stress-mediated apoptosis.
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结核分枝杆菌ESX-1分泌底物蛋白EspC通过内质网应激介导的细胞凋亡促进分枝杆菌存活
DOI：
10.1080/22221751.2020.1861913
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发表时间：
2021-12
影响因子：
13.2
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Guo Q;Bi J;Wang H;Zhang X
摘要 EsxA 由 ESAT-6 分泌系统 1 (ESX-1) 分泌系统分泌，被认为是结核分枝杆菌 (Mtb) 毒力的主要决定因素。然而，各个 ESX-1 底物（例如 EspC）的作用仍不清楚，因为它们与 EsxA 的分泌相互依赖性。在这里，我们验证了 EspC 触发了巨噬细胞中内质网应激介导的细胞凋亡。 EspC 介导的 ER 应激参与促炎细胞因子的产生、细胞内 Ca2+ 的释放和活性氧的积累。 EspC 处理的巨噬细胞中发生线粒体跨膜电位耗散和线粒体外膜透化，导致细胞凋亡。此外，在过表达 EspC 的耻垢分枝杆菌感染的巨噬细胞和小鼠中，ER 应激介导的细胞凋亡被有效诱导。 EspC 过度表达导致巨噬细胞、脾脏和肺部细菌存活率显着增加，并观察到小鼠死亡加速。此外，用凋亡抑制剂预处理显着降低了巨噬细胞中细菌活力的增加。总体而言，我们的结果表明，EspC 是 Mtb-宿主相互作用的重要 ESX-1 蛋白，并且 EspC 诱导的 ER 应激介导的细胞凋亡可能被 Mtb 用于建立和传播感染。鉴于 ESX 系统在 Mtb 发病机制和免疫中的关键作用，我们的研究结果为复杂的宿主-病原体相互作用和 ESX-1 介导的发病机制提供了新的视角。
ABSTRACT EsxA, secreted by the ESAT-6 secretion system 1 (ESX-1) secretion system, is considered the major Mycobacterium tuberculosis (Mtb) virulence determinant. However, the roles of the individual ESX-1 substrates, such as EspC, remain unclear due to their interdependency for secretion with EsxA. Here, we validated that EspC triggered ER stress-mediated apoptosis in macrophages. The EspC-mediated ER stress was involved in pro-inflammatory cytokines generation, intracellular Ca2+ release, and reactive oxygen species accumulation. Mitochondrial transmembrane potential dissipation and mitochondrial outer membrane permeabilization occurred in EspC-treated macrophages, causing apoptosis. Furthermore, ER stress-mediated apoptosis was effectively induced in EspC-overexpressing Mycobacterium smegmatis-infected macrophages and mice. EspC overexpression caused a significant increase in bacterial survival in the macrophages, spleens, and lungs, and accelerated mouse death was observed. Moreover, the increased viability of bacteria in the macrophages was significantly reduced by pretreatment with the apoptosis inhibitor. Overall, our results revealed that EspC is an essential ESX-1 protein for Mtb–host interactions and EspC-induced ER stress-mediated apoptosis may be employed by Mtb to establish and spread infection. Given the critical roles of the ESX systems in Mtb pathogenesis and immunity, our findings offer new perspectives on the complex host-pathogen interactions and mechanisms underlying ESX-1-mediated pathogenesis.
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影响因子：
3.6
作者：
Coros, Abbie;Callahan, Brian;Derbyshire, Keith M.
通讯作者：
Derbyshire, Keith M.
影响因子：
4.6
作者：
Kim, Hee Jung;Jeong, Jae Seok;Kim, So Ri;Park, Seung Yong;Chae, Han Jung;Lee, Yong Chul
通讯作者：
Lee, Yong Chul
DOI：
10.1074/mcp.m112.017533
发表时间：
2012-09
期刊：
Molecular & cellular proteomics : MCP
影响因子：
--
作者：
Champion MM;Williams EA;Kennedy GM;Champion PA
通讯作者：
Champion PA
影响因子：
3.2
作者：
Chen, Jeffrey M.;Zhang, Ming;Cole, Stewart T.
通讯作者：
Cole, Stewart T.
影响因子：
3.2
作者：
Fisher, MA;Plikaytis, BB;Shinnick, TM
通讯作者：
Shinnick, TM