Structurally Distinct Bacterial TBC-like GAPs Link Arf GTPase to Rab1 Inactivation to Counteract Host Defenses
Structurally Distinct Bacterial TBC-like GAPs Link Arf GTPase to Rab1 Inactivation to Counteract Host Defenses
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DOI：
10.1016/j.cell.2012.06.050
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发表时间：
2012-08-31
期刊：
影响因子：
64.5
通讯作者：
Shao, Feng
中科院分区：
文献类型：
--
作者：
Dong, Na;Zhu, Yongqun;Shao, Feng
Rab GTP酶是液泡存活细菌病原体的常见靶标，用于液泡的适当运输。在这里，我们发现，细菌效应器，包括VirA从nonvacuole志贺菌福氏和EspG从胞外肠致病性大肠杆菌（EPEC）港口TBC样双指基序，并表现出强大的RabGAP活动。通过VirA/EspG对Rab 1的特异性失活破坏了ER到高尔基体的运输。S.弗氏菌胞内持久性需要VirA TBC样GAP活性，其介导细菌逃避自噬介导的宿主防御。通过EspG使Rab 1失活严重阻断宿主分泌途径，导致受感染细胞的白细胞介素-8分泌受到抑制。VirA/EspG-Rab 1-GDP-氟化铝复合物的晶体结构突出了精氨酸和谷氨酰胺指状残基的TBC样催化作用，并揭示了不同于TBC结构域的3D结构。Arf 6-EspG-Rab 1三元复合物的结构说明了一种致病性信号传导复合物，其将宿主Arf信号传导重新连接到Rab 1失活。VirA/EspG的结构差异进一步预测了可能广泛存在的TBC样RabGAP效应子抵消各种宿主防御。
Rab GTPases are frequent targets of vacuole-living bacterial pathogens for appropriate trafficking of the vacuole. Here we discover that bacterial effectors including VirA from nonvacuole Shigella flexneri and EspG from extracellular Enteropathogenic Escherichia coli (EPEC) harbor TBC-like dual-finger motifs and exhibits potent RabGAP activities. Specific inactivation of Rab1 by VirA/EspG disrupts ER-to-Golgi trafficking. S. flexneri intracellular persistence requires VirA TBC-like GAP activity that mediates bacterial escape from autophagy-mediated host defense. Rab1 inactivation by EspG severely blocks host secretory pathway, resulting in inhibited interleukin-8 secretion from infected cells. Crystal structures of VirA/EspG-Rab1-GDP-aluminum fluoride complexes highlight TBC-like catalytic role for the arginine and glutamine finger residues and reveal a 3D architecture distinct from that of the TBC domain. Structure of Arf6-EspG-Rab1 ternary complex illustrates a pathogenic signaling complex that rewires host Arf signaling to Rab1 inactivation. Structural distinctions of VirA/EspG further predict a possible extensive presence of TBC-like RabGAP effectors in counteracting various host defenses.