Shigella IcsA Activation of Actin Assembly by N-WASP

描述(由申请人提供) 志贺氏菌属是导致大约100万人死亡的细菌病原体吗？ 全球每年有1.63亿例腹泻和痢疾病例， 主要是在儿童中。志贺氏菌通过入侵和传播致病 通过结肠上皮。志贺氏菌通过进入猪瘟的细胞质传播 宿主细胞，并诱导在细菌体内组装肌动蛋白尾巴。 肌动蛋白尾部的形成涉及细胞肌动蛋白组装的细菌募集 机械设备。戈德堡博士的实验室已经证明志贺氏菌蛋白 ICSA足以调解这一进程。ICSA利用细胞内的CDC42 肌动蛋白组装的信号转导途径，已被证明是 在丝状孢子的形成中很重要。这一细胞通路涉及cdc42。 Wiskott-Aldrich综合征蛋白(WASP)家族成员的激活。 激活的WASP家族成员激活Arp213复合体，使肌动蛋白成核，并 聚合新的细丝，Arp2/3以700度的角度与其交联 已经存在的细丝。已知ICSA绑定WASP的成员N-WASP 然而，它激活N-WASP的机制尚不清楚。ICSA是 对志贺氏菌的致病力至关重要。我们建议将其机制描述为 L CSA激活N-WASP。我们将鉴定N-WASP和LCSA的残留物 对N-WASP的LcSA结合或LcSA激活都很重要。到时候我们会的 测试N-WASP是否被LCSA以类似于其激活的方式激活 由Cdc42。这些研究将为深入了解这两种分子机制提供帮助。 志贺氏菌致病机制及0dc42介导肌动蛋白的分子机制 集合。

DESCRIPTION (provided by applicant) Shigella spp. are bacterial pathogens that cause an estimated I million deaths and 163 million cases of diarrhea and dysentery annually worldwide, predominantly in children. Shigella cause disease by invading and spreading through the colonic epithelium. Shigella spread by entering the cytoplasm of the host cell and inducing the assembly of an actin tail on the bacterial body. Actin tail formation involves bacterial recruitment of cellular actin assembly machinery. Dr. Goldberg laboratory has demonstrated that the Shigella protein IcsA is sufficient to mediate this process. IcsA utilizes the cellular Cdc42 signal transduction pathway for actin assembly, which has been shown to be important in filopodia formation. This cellular pathway involves Cdc42 activation of members of the Wiskott-Aldrich syndrome protein (WASP) family. Activated WASP family members activate the Arp213 complex to nucleate actin and polymerize new filaments, which Arp2/3 cross-links at 700 angles to pre-existing filaments. IcsA is known to bind N-WASP, a member of the WASP family, yet the mechanism by which it activates N-WASP is unknown. IcsA is essential to Shigella virulence. We propose to characterize the mechanism of lcsA activation of N-WASP. We will identify residues of N-WASP and lcsA that are important to either lcsA binding or lcsA activation of N-WASP. We will then test whether N-WASP is activated by lcsA in a fashion similar to its activation by Cdc42. These studies will provide insight into both the molecular mechanisms of Shigella pathogenesis and the molecular mechanisms of 0dc42-mediated actin assembly.