The regulatory functions of ESX-1 substrates, EspE and EspF, are separable from secretion.

IF 2.7 3区 生物学 Q3 MICROBIOLOGY
Journal of Bacteriology Pub Date : 2024-09-19 Epub Date: 2024-08-13 DOI:10.1128/jb.00271-24
Rebecca J Prest, Konstantin V Korotkov, Patricia A Champion
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引用次数: 0

Abstract

Pathogenic mycobacteria are a significant global health burden. The ESX-1 secretion system is essential for mycobacterial pathogenesis. The secretion of ESX-1 substrates is required for phagosomal lysis, which allows the bacteria to enter the macrophage cytoplasm, induce a Type I IFN response, and spread to new host cells. EspE and EspF are dual-functioning ESX-1 substrates. Inside the mycobacterial cell, they regulate transcription of ESX-1-associated genes. Following secretion, EspE and EspF are essential for lytic activity. The link between EspE/F secretion and regulatory function has not been investigated. We investigated the relationship between EspE and EspF using molecular genetics in Mycobacterium marinum, a non-tuberculous mycobacterial species that serves as an established model for ESX-1 secretion and function in Mycobacterium tuberculosis. Our data support that EspE and EspF, which require each other for secretion, directly interact. The disruption of the predicted protein-protein interaction abrogates hemolytic activity and secretion but does not impact their gene regulatory activities in the mycobacterial cell. In addition, we predict a direct protein-protein interaction between the EsxA/EsxB heterodimer and EspF. Our data support that the EspF/EsxA interaction is also required for hemolytic activity and EspE secretion. Our study sheds light on the intricate molecular mechanisms governing the interactions between ESX-1 substrates, regulatory function, and ESX-1 secretion, moving the field forward.IMPORTANCETuberculosis (TB), caused by Mycobacterium tuberculosis, is a historical and pervasive disease responsible for millions of deaths annually. The rise of antibiotic and treatment-resistant TB, as well as the rise of infection by non-tuberculous mycobacterial species, calls for a better understanding of pathogenic mycobacteria. The ESX-1 secreted substrates, EspE and EspF, are required for mycobacterial virulence and may be responsible for phagosomal lysis. This study focuses on the mechanism of EspE and EspF secretion from the mycobacterial cell.

ESX-1 底物 EspE 和 EspF 的调节功能可与分泌功能分开。
致病分枝杆菌是全球健康的重大负担。ESX-1 分泌系统对分枝杆菌的致病至关重要。ESX-1底物的分泌是吞噬体裂解所必需的,吞噬体裂解可使细菌进入巨噬细胞胞质,诱导I型IFN反应,并扩散到新的宿主细胞。EspE 和 EspF 是具有双重功能的 ESX-1 底物。在分枝杆菌细胞内,它们调节 ESX-1 相关基因的转录。分泌后,EspE 和 EspF 对溶菌活动至关重要。EspE/F 的分泌与调控功能之间的联系尚未得到研究。我们利用分子遗传学研究了海洋分枝杆菌(Mycobacterium marinum)中 EspE 和 EspF 之间的关系,海洋分枝杆菌是一种非结核分枝杆菌,是 ESX-1 分泌和结核分枝杆菌功能的既定模型。我们的数据证明,EspE 和 EspF 在分泌过程中需要彼此直接相互作用。破坏预测的蛋白-蛋白相互作用会削弱溶血活性和分泌,但不会影响它们在分枝杆菌细胞中的基因调控活动。此外,我们还预测 EsxA/EsxB 异源二聚体与 EspF 之间存在直接的蛋白-蛋白相互作用。我们的数据支持 EspF/EsxA 相互作用也是溶血活性和 EspE 分泌所必需的。我们的研究揭示了支配 ESX-1 底物、调节功能和 ESX-1 分泌之间相互作用的复杂分子机制,推动了该领域的发展。随着抗生素和耐药性结核病的增多以及非结核分枝杆菌感染的增加,人们需要更好地了解致病分枝杆菌。ESX-1分泌的底物EspE和EspF是分枝杆菌毒力所必需的,并可能负责吞噬体裂解。本研究的重点是 EspE 和 EspF 从分枝杆菌细胞中分泌的机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Bacteriology
Journal of Bacteriology 生物-微生物学
CiteScore
6.10
自引率
9.40%
发文量
324
审稿时长
1.3 months
期刊介绍: The Journal of Bacteriology (JB) publishes research articles that probe fundamental processes in bacteria, archaea and their viruses, and the molecular mechanisms by which they interact with each other and with their hosts and their environments.
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