Inhibition of WAVE Regulatory Complex Activation by a Bacterial Virulence Effector Counteracts Pathogen Phagocytosis.
Inhibition of WAVE Regulatory Complex Activation by a Bacterial Virulence Effector Counteracts Pathogen Phagocytosis.
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DOI：
10.1016/j.celrep.2016.09.039
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发表时间：
2016-10-11
期刊：
影响因子：
8.8
通讯作者：
Koronakis V
中科院分区：
文献类型：
--
作者：
Humphreys D;Singh V;Koronakis V
为了建立致病性，细菌必须通过肌动蛋白细胞骨架的重塑来逃避吞噬作用。我们发现巨噬细胞通过由WAVE调节复合体（WRC）、小gtpase Arf和Rac1以及Arf1激活剂ARNO介导的肌动蛋白聚合促进病原体吞噬。为了建立细胞外感染，肠致病性（EPEC）和肠出血性（EHEC）大肠杆菌通过向宿主细胞注射毒力效应物来劫持肌动蛋白细胞骨架。在这里，我们发现毒力效应物EspG抵消了wrc依赖性吞噬作用，使EPEC和EHEC留在细胞外。通过重构膜相关的肌动蛋白聚合，我们发现EspG通过两种机制抑制WRC的激活：EspG与Arf6的相互作用阻断了ARNO的信号传导，而EspG与Arf1的结合阻碍了与Rac1的合作，从而抑制了WRC的募集和激活。研究EspG的干扰模式揭示了WRC激活所需的Arf1位点和促进病原体逃避先天宿主防御的机制。WAVE调控复合体（WRC）和Arf和Rac1直接吞噬EPEC和EHEC毒力效应物EspG抑制WRC对抗病原体吞噬EspG阻断Arf6信号传递给激活Arf1的ARNO EspG阻断Arf1与Rac1和WRC激活的协同作用Humphreys等人发现肠致病性和肠出血性大肠杆菌的毒力效应物EspG通过抑制WAVE调控复合体（WRC）的激活来抑制病原体吞噬。EspG将小gtpase Arf1和Arf6与Rac1分离，从而启动wrc依赖性肌动蛋白聚合。
To establish pathogenicity, bacteria must evade phagocytosis directed by remodeling of the actin cytoskeleton. We show that macrophages facilitate pathogen phagocytosis through actin polymerization mediated by the WAVE regulatory complex (WRC), small GTPases Arf and Rac1, and the Arf1 activator ARNO. To establish extracellular infections, enteropathogenic (EPEC) and enterohaemorrhagic (EHEC) Escherichia coli hijack the actin cytoskeleton by injecting virulence effectors into the host cell. Here, we find that the virulence effector EspG counteracts WRC-dependent phagocytosis, enabling EPEC and EHEC to remain extracellular. By reconstituting membrane-associated actin polymerization, we find that EspG disabled WRC activation through two mechanisms: EspG interaction with Arf6 blocked signaling to ARNO while EspG binding of Arf1 impeded collaboration with Rac1, thereby inhibiting WRC recruitment and activation. Investigating the mode of EspG interference revealed sites in Arf1 required for WRC activation and a mechanism facilitating pathogen evasion of innate host defenses. WAVE regulatory complex (WRC) and Arf and Rac1 direct phagocytosis of EPEC and EHEC Virulence effector EspG inhibits the WRC to counteract pathogen phagocytosis EspG blocks Arf6 signaling to ARNO that activates Arf1 EspG blocks Arf1 collaboration with Rac1 and WRC activation Humphreys et al. find that the virulence effector EspG of enteropathogenic and enterohaemorrhagic Escherichia coli inhibits pathogen phagocytosis by inhibiting activation of the WAVE regulatory complex (WRC). EspG uncouples the small GTPases Arf1 and Arf6 from Rac1, thus initiating WRC-dependent actin polymerization.
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肌动蛋白调节波复合物的结构和控制。
影响因子：
64.8
作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
4.8
作者：
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