Intracellular periodontal pathogen exploits recycling pathway to exit from infected cells
Intracellular periodontal pathogen exploits recycling pathway to exit from infected cells
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DOI：
10.1111/cmi.12551
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发表时间：
2016-07
影响因子：
3.4
通讯作者：
Hiroki Takeuchi;Akihiko Takada;M. Kuboniwa;A. Amano
中科院分区：
文献类型：
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作者：
Hiroki Takeuchi;Akihiko Takada;M. Kuboniwa;A. Amano
尽管人类牙龈上皮可以防止牙周细菌的侵入，但最著名的牙周病原体牙龈卟啉单胞菌能够侵入牙龈上皮细胞并穿过上皮屏障进入更深的组织。我们之前报道过细胞内牙龈卟啉单胞菌通过回收途径从牙龈上皮细胞中排出。然而，潜在的分子过程仍然未知。在本研究中，我们发现位于早期内体的病原体会招募 VAMP2 和 Rab4A。人们发现 VAMP2 特异性定位于早期内体，但其在哺乳动物细胞中的定位仍不清楚。发现 VAMP2 的单个跨膜结构域对于定位在牙龈上皮细胞中含有牙龈卟啉单胞菌的早期内体中是必要且充分的。 VAMP2 与 EXOC2/Sec5 和 EXOC3/Sec6 形成复合物，而 Rab4A 介导 EXOC 复合物的解离，然后招募 RUFY1/Rabip4、Rab4A 效应子和 Rab14。 VAMP2 或 Rab4A 的耗竭导致细菌在早期内体中积聚，并干扰细菌从受感染细胞中排出。研究表明，这些新的动态使得牙龈卟啉单胞菌能够利用快速回收途径，促进细菌进一步渗透牙龈组织。
Although human gingival epithelium prevents intrusions by periodontal bacteria, Porphyromonas gingivalis, the most well‐known periodontal pathogen, is able to invade gingival epithelial cells and pass through the epithelial barrier into deeper tissues. We previously reported that intracellular P. gingivalis exits from gingival epithelial cells via a recycling pathway. However, the underlying molecular process remains unknown. In the present study, we found that the pathogen localized in early endosomes recruits VAMP2 and Rab4A. VAMP2 was found to be specifically localized in early endosomes, although its localization remained unclear in mammalian cells. A single transmembrane domain of VAMP2 was found to be necessary and sufficient for localizing in early endosomes containing P. gingivalis in gingival epithelial cells. VAMP2 forms a complex with EXOC2/Sec5 and EXOC3/Sec6, whereas Rab4A mediates dissociation of the EXOC complex followed by recruitment of RUFY1/Rabip4, Rab4A effector, and Rab14. Depletion of VAMP2 or Rab4A resulted in accumulation of bacteria in early endosomes and disturbed bacterial exit from infected cells. It is suggested that these novel dynamics allow P. gingivalis to exploit fast recycling pathways promoting further bacterial penetration of gingival tissues.