The Francisella O-antigen mediates survival in the macrophage cytosol via autophagy avoidance.
The Francisella O-antigen mediates survival in the macrophage cytosol via autophagy avoidance.
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DOI：
10.1111/cmi.12246
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发表时间：
2014-06
影响因子：
3.4
通讯作者：
Celli J
中科院分区：
文献类型：
--
作者：
Case ED;Chong A;Wehrly TD;Hansen B;Child R;Hwang S;Virgin HW;Celli J
自噬是对细胞内寄生虫的一种关键的先天性免疫应答，其促进在胞质溶胶中或在受损的空泡内检测到寄生虫后将其递送至降解的溶酶体。像李斯特菌和志贺氏菌一样，它们使用特定的机制来避免自噬检测和捕获，细菌病原体土拉弗朗西斯菌在巨噬细胞的胞质溶胶内增殖，而没有明显的自噬控制。为了研究弗朗西斯菌如何逃避自噬，我们筛选了弗朗西斯菌的文库。土拉热亚种通过显微镜观察在GFP-LC 3表达鼠巨噬细胞中的土拉热菌Schu S4 HimarFT转座子突变体，用于吞噬体逃逸后定位在自噬空泡内的克隆。11个克隆在感染后6小时表现出自噬捕获，其HimarFT插入聚集到参与脂多糖和荚膜O-抗原生物合成的4个遗传位点。与HimarFT突变体一致，两个代表性基因座FTT 1236和FTT 1448 c（manC）的框内缺失突变体（缺乏LPS和荚膜O-抗原）经历吞噬体逃逸，但从宿主胞质溶胶中清除。与野生型弗朗西斯菌不同，O抗原缺失突变体被遍在蛋白化，并在胞质清除之前招募自噬衔接子p62/SQSTM 1和LC 3。自噬缺陷的巨噬细胞部分支持两种突变体的复制，表明O-抗原缺乏弗朗西斯菌是由自噬控制的。这些数据证明了这种细菌表面多糖对自噬的细胞内保护作用。
Autophagy is a key innate immune response to intracellular parasites that promotes their delivery to degradative lysosomes following detection in the cytosol or within damaged vacuoles. Like Listeria and Shigella, which use specific mechanisms to avoid autophagic detection and capture, the bacterial pathogen Francisella tularensis proliferates within the cytosol of macrophages without demonstrable control by autophagy. To examine how Francisella evades autophagy, we screened a library of F. tularensis subsp. tularensis Schu S4 HimarFT transposon mutants in GFP-LC3-expressing murine macrophages by microscopy for clones localised within autophagic vacuoles after phagosomal escape. Eleven clones showed autophagic capture at six hours post-infection, whose HimarFT insertions clustered to four genetic loci involved in lipopolysaccharidic and capsular O-antigen biosynthesis. Consistent with the HimarFT mutants, in-frame deletion mutants of two representative loci, FTT1236 and FTT1448c (manC), lacking both LPS and capsular O-antigen, underwent phagosomal escape but were cleared from the host cytosol. Unlike wild type Francisella, the O-antigen deletion mutants were ubiquitinated, and recruited the autophagy adaptor p62/SQSTM1 and LC3 prior to cytosolic clearance. Autophagy-deficient macrophages partially supported replication of both mutants, indicating that O-antigen-lacking Francisella are controlled by autophagy. These data demonstrate the intracellular protective role of this bacterial surface polysaccharide against autophagy.
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LRR和环域蛋白LRSAM1是一种E3连接酶，对于细胞内沙门氏菌的泛素依赖性自噬至关重要。
影响因子：
30.3
作者：
Huett A;Heath RJ;Begun J;Sassi SO;Baxt LA;Vyas JM;Goldberg MB;Xavier RJ
通讯作者：
Xavier RJ
影响因子：
6.7
作者：
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通讯作者：
Cossart P
影响因子：
3.4
作者：
Peng K;Broz P;Jones J;Joubert LM;Monack D
通讯作者：
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影响因子：
3
作者：
Prior, JL;Prior, RG;Titball, RW
通讯作者：
Titball, RW
影响因子：
4.7
作者：
Gal J;Ström AL;Kwinter DM;Kilty R;Zhang J;Shi P;Fu W;Wooten MW;Zhu H
通讯作者：
Zhu H