肠致病性大肠杆菌效应物 EspF 的 C 端富含脯氨酸的重复序列足以消耗紧密连接膜蛋白以及与早期和再循环内体的相互作用。

IF 4.3 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Imran Ansari, Anupam Mandal, Kritika Kansal, Pangertoshi Walling, Sumbul Khan, Saima Aijaz
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引用次数: 0

摘要

背景:在发展中国家,肠致病性大肠杆菌(EPEC)会导致婴儿急性腹泻,造成严重的发病率和死亡率。EPEC 利用三型分泌系统将 20 多种效应物转运到宿主肠道细胞中。据报道,其中至少有四种效应物(即 EspF、Map、EspG1/G2 和 NleA)可破坏肠道紧密连接屏障。我们早些时候曾报道,在 MDCK 细胞中表达 EspF 和 Map 会导致 TJ 膜蛋白耗竭,损害肠道屏障的完整性。在本研究中,我们研究了EspF C端富含脯氨酸的重复序列(PRR)在消耗紧密连接膜蛋白中的作用,并确定了通过这些重复序列与EspF相互作用的关键内吞标志物:我们生成了突变体EspF蛋白,它们在EspF的N端缺少一个或多个富脯氨酸重复序列(PRRs),并研究了它们的表达对紧连接膜蛋白细胞定位的影响。在表达突变型 EspF 蛋白的细胞裂解液中,我们发现 EspF 的 C 端 PRRs 足以导致 TJ 膜蛋白的耗竭。牵引试验显示,PRRs介导了与TJ适配蛋白ZO-1和ZO-2以及参与内吞的蛋白(如caveolin-1、Rab5A和Rab11)的相互作用:我们的研究证明了 EspF 的富脯氨酸重复序列在 TJ 膜蛋白耗竭中的直接作用,以及 PRRs 可能参与宿主蛋白的内吞。新的治疗策略可以针对这些 PRR 结构域,防止 EPEC 感染时出现肠屏障功能障碍。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The C-terminal proline-rich repeats of Enteropathogenic E. coli effector EspF are sufficient for the depletion of tight junction membrane proteins and interactions with early and recycling endosomes.

Background: Enteropathogenic E. coli (EPEC) causes acute infantile diarrhea accounting for significant morbidity and mortality in developing countries. EPEC uses a type three secretion system to translocate more than twenty effectors into the host intestinal cells. At least four of these effectors, namely EspF, Map, EspG1/G2 and NleA, are reported to disrupt the intestinal tight junction barrier. We have reported earlier that the expression of EspF and Map in MDCK cells causes the depletion of the TJ membrane proteins and compromises the integrity of the intestinal barrier. In the present study, we have examined the role of the proline-rich repeats (PRRs) within the C-terminus of EspF in the depletion of the tight junction membrane proteins and identified key endocytosis markers that interact with EspF via these repeats.

Results: We generated mutant EspF proteins which lacked one or more proline-rich repeats (PRRs) from the N-terminus of EspF and examined the effect of their expression on the cellular localization of tight junction membrane proteins. In lysates derived from cells expressing the mutant EspF proteins, we found that the C-terminal PRRs of EspF are sufficient to cause the depletion of TJ membrane proteins. Pull-down assays revealed that the PRRs mediate interactions with the TJ adaptor proteins ZO-1 and ZO-2 as well as with the proteins involved in endocytosis such as caveolin-1, Rab5A and Rab11.

Conclusions: Our study demonstrates the direct role of the proline-rich repeats of EspF in the depletion of the TJ membrane proteins and a possible involvement of the PRRs in the endocytosis of host proteins. New therapeutic strategies can target these PRR domains to prevent intestinal barrier dysfunction in EPEC infections.

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来源期刊
Gut Pathogens
Gut Pathogens GASTROENTEROLOGY & HEPATOLOGY-MICROBIOLOGY
CiteScore
7.70
自引率
2.40%
发文量
43
期刊介绍: Gut Pathogens is a fast publishing, inclusive and prominent international journal which recognizes the need for a publishing platform uniquely tailored to reflect the full breadth of research in the biology and medicine of pathogens, commensals and functional microbiota of the gut. The journal publishes basic, clinical and cutting-edge research on all aspects of the above mentioned organisms including probiotic bacteria and yeasts and their products. The scope also covers the related ecology, molecular genetics, physiology and epidemiology of these microbes. The journal actively invites timely reports on the novel aspects of genomics, metagenomics, microbiota profiling and systems biology. Gut Pathogens will also consider, at the discretion of the editors, descriptive studies identifying a new genome sequence of a gut microbe or a series of related microbes (such as those obtained from new hosts, niches, settings, outbreaks and epidemics) and those obtained from single or multiple hosts at one or different time points (chronological evolution).
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