Mycobacterium tuberculosis ESX-1-secreted substrate protein EspC promotes mycobacterial survival through endoplasmic reticulum stress-mediated apoptosis

Guo, Qinglong1,2; Bi, Jing1,3; Wang, Honghai1; Zhang, Xuelian1,4

2021

10.1080/22221751.2020.1861913

EMERGING MICROBES & INFECTIONS   影响因子和分区

2222-1751

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.

M tuberculosis ESX secretion-associated protein C endoplasmic reticulum stress caspase activation mitochondria damage macrophage apoptosis

SCI

英语

其他

National Key R&D Program of China["2016YFA0500600","SKLGE-1912"] ; Key scientific and technological projects of Xinjiang production and Construction Corps[2020AB015] ; National Natural Science Foundation of China[81673482,81971898]

Immunology ; Microbiology

Immunology ; Microbiology

WOS:000610541400001

TAYLOR & FRANCIS LTD

Web of Science

1.Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai 200438, Peoples R China
2.South Univ Sci & Technol China, Shenzhen Peoples Hosp 3, Natl Clin Res Ctr Infect Dis TB, Shenzhen, Peoples R China
3.Fudan Univ, Sch Basic Med Sci, Minist Educ & Hlth, Key Lab Med Mol Virol, Shanghai, Peoples R China
4.Fudan Univ, Shanghai Engn Res Ctr Ind Microorganisms, Shanghai 200032, Peoples R China

Guo, Qinglong,Bi, Jing,Wang, Honghai,et al. Mycobacterium tuberculosis ESX-1-secreted substrate protein EspC promotes mycobacterial survival through endoplasmic reticulum stress-mediated apoptosis[J]. EMERGING MICROBES & INFECTIONS,2021,10(1).

Guo, Qinglong,Bi, Jing,Wang, Honghai,&Zhang, Xuelian.(2021).Mycobacterium tuberculosis ESX-1-secreted substrate protein EspC promotes mycobacterial survival through endoplasmic reticulum stress-mediated apoptosis.EMERGING MICROBES & INFECTIONS,10(1).

Guo, Qinglong,et al."Mycobacterium tuberculosis ESX-1-secreted substrate protein EspC promotes mycobacterial survival through endoplasmic reticulum stress-mediated apoptosis".EMERGING MICROBES & INFECTIONS 10.1(2021).