The ESCRT and autophagy machineries cooperate to repair ESX-1-dependent damage at the Mycobacterium-containing vacuole but have opposite impact on containing the infection
The ESCRT and autophagy machineries cooperate to repair ESX-1-dependent damage at the Mycobacterium-containing vacuole but have opposite impact on containing the infection
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DOI：
10.1371/journal.ppat.1007501
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发表时间：
2018-12-01
期刊：
影响因子：
6.7
通讯作者：
Soldati, Thierry
中科院分区：
文献类型：
--
作者：
Lopez-Jimenez, Ana T.;Cardenal-Munoz, Elena;Soldati, Thierry
吞噬细胞捕获并杀死杀菌吞噬体内的大多数入侵微生物，但一些病原体通过破坏隔室并逃逸到胞质溶胶来破坏杀灭作用。为了防止病原体毒力和宿主防御因子的泄漏以及细菌逃逸，宿主细胞必须遏制和修复细胞膜损伤，或最终消灭胞质细菌。所有真核细胞都参与各种修复机制，以确保质膜完整性和细胞器的正确划分，包括运输所需的内体分选复合体 (ESCRT) 和自噬机制。我们发现，在海分枝杆菌感染盘基网柄菌期间，ESCRT-I 成分 Tsg101、ESCRT-III 蛋白 Snf7/Chmp4/Vps32 和 AAA-ATPase Vps4 被募集到含分枝杆菌液泡的损伤位点。有趣的是，损伤分别招募 ESRT 和自噬机制。此外，募集 Vps32 和 Vps4 来修复无菌膜损伤取决于 Tsg101，但似乎与 Ca2+ 无关。最后，在 Tsg101 缺失的情况下，M. marinum 会过早地进入细胞质，而细胞质中的自噬机制会限制其生长。我们认为 ESCRT 具有进化保守的功能，可以修复小膜损伤并将细胞内病原体包含在完整的隔室中。
Phagocytic cells capture and kill most invader microbes within the bactericidal phagosome, but some pathogens subvert killing by damaging the compartment and escaping to the cytosol. To prevent the leakage of pathogen virulence and host defence factors, as well as bacteria escape, host cells have to contain and repair the membrane damage, or finally eliminate the cytosolic bacteria. All eukaryotic cells engage various repair mechanisms to ensure plasma membrane integrity and proper compartmentalization of organelles, including the Endosomal Sorting Complex Required for Transport (ESCRT) and autophagy machineries. We show that during infection of Dictyostelium discoideum with Mycobacterium marinum, the ESCRT-I component Tsg101, the ESCRT-III protein Snf7/Chmp4/Vps32 and the AAA-ATPase Vps4 are recruited to sites of damage at the Myco-bacterium-containing vacuole. Interestingly, damage separately recruits the ESCRT and the autophagy machineries. In addition, the recruitment of Vps32 and Vps4 to repair sterile membrane damage depends on Tsg101 but appears independent of Ca2+. Finally, in absence of Tsg101, M. marinum accesses prematurely the cytosol, where the autophagy machinery restricts its growth. We propose that ESCRT has an evolutionary conserved function to repair small membrane damage and to contain intracellular pathogens in intact compartments.