Unraveling the role of host endocytic proteins in pedestal formation during enteropathogenic Escherichia coli infection.
Unraveling the role of host endocytic proteins in pedestal formation during enteropathogenic Escherichia coli infection.
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揭示宿主内吞蛋白在肠致病性大肠杆菌感染期间基座形成中的作用。
DOI：
10.1093/infdis/jir391
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
DuPont,HerbertL
中科院分区：
文献类型：
--
作者：
Darkoh,Charles;DuPont,HerbertL
肠致病性大肠杆菌（EPEC）是儿童腹泻的主要原因之一，在发展中地区每年造成200万儿童死亡。EPEC是一个相关的附着和清除病原体家族的原型成员，它使用各种毒力蛋白效应物劫持宿主内吞成分形成基座状结构。基底形成是EPEC发病机制的一个标志。除了提供EPEC与宿主细胞表面的亲密连接（可能是为了避免在随后的水样腹泻宿主反应中脱位）之外，基座的确切功能尚不确定。EPEC的基因组包含一个致病性岛，其中包含编码成功定植宿主所需蛋白质的基因。这个岛包括编码III型分泌系统（T3SS）、束形成菌毛、伴侣蛋白、调节蛋白、细菌外膜蛋白内膜素以及其他几种效应蛋白的基因。EPEC释放这些效应蛋白来改变参与内吞作用的宿主蛋白。宿主内吞蛋白已被确定为EPEC的靶标，包括网格蛋白、接头蛋白-2 （AP-2）、动力蛋白-2、Eps15和epsin蛋白家族[2,3]。epec介导的篡夺宿主内吞相关蛋白的机制以及这些靶向蛋白在基台形成过程中所起的作用尚不清楚。Lin等人在本期Journal中报道，基于对人类细胞系感染EPEC过程中Eps15和epsin1蛋白定位的研究，除了网格蛋白外，基座形成还需要Eps15和epsin1蛋白，但不需要AP-2蛋白。为了增加它们的生存和传播，革兰氏阴性细菌使用T3SS将毒力效应蛋白直接引入真核宿主。这些高度保守的超分子复合物跨越细菌膜，穿过细胞外空间，穿透宿主细胞膜，使毒力因子能够直接从细菌细胞质转运。细菌效应蛋白结构各异，具有多种功能，如诱导或预防吞噬、抑制免疫系统、调节宿主细胞周期和死亡。T3SS在EPEC[5]以及其他致病菌如耶尔森氏菌、志贺氏菌、假单胞菌和沙门氏菌[6]感染过程中起着至关重要的作用。易位内膜受体（Tir）是EPEC感染过程中对基底形成至关重要的效应蛋白之一。亲密依恋需要细菌外膜蛋白intimin[7]。该蛋白通过与Tir结合介导EPEC与宿主细胞的附着，Tir通过T3SS转运到宿主细胞膜上[8,9]。EPEC对Tir的利用强调了病原体将自身受体注入宿主而不是依赖宿主衍生受体的适应策略。这种策略可能使EPEC能够感染广泛的物种和不同的组织。Tir有2个跨膜结构域，中间有一个区域形成胞外环，而n端和c端位于细胞[7]内。内膜素与细胞外环结合，这种内膜素与tir的相互作用对于基座形成和肌动蛋白丝聚合[9]至关重要。在体外，内膜素也通过其c端区以不依赖于tir的方式与宿主细胞结合，这表明宿主上皮细胞[10]上可能存在不止一种内膜素受体。Tir-内膜素结合将病原体锚定在上皮细胞表面并招募宿主细胞激酶来诱导Tir
Enteropathogenic Escherichia coli (EPEC) is one of the leading causes of pediatric diarrhea, contributing to an overall burden of 2 million annual deaths in children in developing regions [1]. EPEC is a prototypic member of a related family of attaching and effacing pathogens that use various virulence protein effectors to hijack the host endocytic components to form pedestal-like structures. Pedestal formation is a hallmark of EPEC pathogenesis. Other than providing an intimate attachment of EPEC to the host cell surface, presumably to avoid being dislocated during the subsequent host response of watery diarrhea, the exact function of pedestals is uncertain. The genome of EPEC contains a pathogenicity island comprising genes that encode proteins required for successful colonization of the host. This island includes genes that code for a type III secretion system (T3SS), bundle-forming pilus, chaperones, regulatory proteins, and the bacterial outer membrane protein intimin, as well as several other effector proteins. EPEC releases these effector proteins to alter the host proteins involved in endocytosis. Host endocytic proteins that have been identified to be targeted by EPEC include clathrin, adaptor protein-2 (AP-2), dynamin-2, Eps15, and a family of epsin proteins [2, 3]. The mechanism of EPEC-mediated usurpation of the host endocytosisassociated proteins and the role these targeted proteins play during pedestal formation are poorly understood. Lin et al [4] report in this issue of the Journal that in addition to clathrin, pedestal formation also requires Eps15 and epsin1 but not AP-2, based on their investigation of the localization of these proteins during EPEC infection of human cell lines. To augment their survival and dissemination, Gram-negative bacteria use the T3SS to introduce virulence effector proteins directly into their eukaryotic host. These highly conserved supramolecular complexes span the bacterial membranes, cross the extracellular space, and penetrate host cell membranes, enabling virulence factors to be translocated directly from the bacterial cytoplasm. Bacterial effector proteins vary in structure and demonstrate a wide range of functions such as induction or prevention of phagocytosis, dampening of the immune system, regulation of the host’s cell cycle, and death. T3SS plays a vital role during infection by EPEC [5], as well as other pathogenic bacteria such as Yersinia spp, Shigella spp, Pseudomonas spp, and Salmonella spp [6]. One of the effector proteins that are crucial in pedestal formation during EPEC infection is the translocated intimin receptor (Tir). Intimate attachment requires the outer bacterial membrane protein intimin [7]. This protein mediates attachment of EPEC to the host cell by binding to Tir, which is translocated into the host cell membrane via the T3SS [8, 9]. Utilization of Tir by EPEC underscores an adaptation strategy of a pathogen injecting its own receptor into its host instead of depending on a hostderived receptor. This strategy perhaps enables EPEC to infect a wide range of species and different tissues. Tir has 2 transmembrane domains with an intervening region that forms an extracellular loop while the N-and C-terminal regions are located within the cell [7]. Intimin binds to the extracellular loop, and this intimin-Tir interaction is essential for pedestal formation and actin filament polymerization [9]. Intimin also binds to host cells in vitro through its C-terminal region in a Tirindependent manner, suggesting that more than one receptor for intimin may be present on host epithelial cells [10]. Tir-intimin binding anchors the pathogen to the epithelial cell surface and recruits host cell kinases to induce Tir
影响因子：
5.4
作者：
Marlovits, Thomas C.;Stebbins, C. Erec
通讯作者：
Stebbins, C. Erec
病原细菌触发上皮信号形成功能性细菌受体，介导肌动蛋白伪足的形成。
DOI：
10.1002/j.1460-2075.1996.tb00621.x
发表时间：
1996
期刊：
The EMBO Journal
影响因子：
--
作者：
Ilan;Rosenshine;S. Ruschkowski;Markus Stein;D. Reinscheid;Scott D. MihIs;B. Finlay
通讯作者：
B. Finlay
影响因子：
3.1
作者：
Kenny, B;Warawa, J
通讯作者：
Warawa, J