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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Listeria monocytogenes phosphatidylinositol-specific phospholipase C has evolved for virulence by greatly reduced activity on GPI anchors
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Listeria monocytogenes phosphatidylinositol-specific phospholipase C has evolved for virulence by greatly reduced activity on GPI anchors

机译：单核细胞增生李斯特菌磷脂酰肌醇特异性磷脂酶C通过大大降低对GPI锚的活性而具有毒性

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摘要

Listeria monocytogenes phosphatidylinositol-specific phospholipase C (PI-PLC) plays a critical role in escape of this human pathogen from host cell vacuoles. Unlike classical bacterial PI-PLCs, the L. monocytogenes enzyme has very weak activity on glycosylphosphaticlylinositol (GPI)-anchored proteins. Previous crystal structure analysis has revealed that a small beta-strand (Vb) is present in Bacillus cereus PI-PLC and is absent in the enzyme from L. monocytogenes. This Vb beta-strand in B. cereus PI-PLC forms contacts with the glycan linker of GPI anchors, which presumably increases its activity on GPI-anchored proteins. In this study, we show that, of all known bacterial PI-PLCs, those from listeriae are the only ones that lack the P-strand. Expression by L. monocytogenes of B. cereus PI-PLC, which has strong activity on GPI-anchored proteins, inhibited bacterial escape from a vacuole and cell-to-cell spread, resulting in greatly reduced virulence in mice. Deletion of the Vb beta-strand from B. cereus PI-PLC abolished its ability to cleave GPI-anchored proteins, decreased its inhibitory effects, and increased its virulence in mice. These results strongly suggest that L. monocytogenes PI-PLC has evolved as an important determinant of L. monocytogenes pathogenesis by absence of the Vb beta-strand, thus leading to greatly reduced activity on GPI-anchored proteins.
机译：单核细胞增生李斯特菌磷脂酰肌醇特异性磷脂酶C（PI-PLC）在这种人类病原体从宿主细胞液泡中逃逸中起关键作用。与经典的细菌PI-PLC不同，单核细胞增生李斯特氏菌酶对糖基磷酸磷脂酰肌醇（GPI）锚定的蛋白质的活性非常弱。先前的晶体结构分析表明，蜡样芽胞杆菌PI-PLC中存在一个小的β链（Vb），而单核细胞增生李斯特氏菌的酶中不存在该β链。蜡状芽孢杆菌PI-PLC中的Vbβ链与GPI锚的聚糖接头形成接触，这可能会增加其对GPI锚定蛋白质的活性。在这项研究中，我们表明，在所有已知的细菌PI-PLC中，仅李斯特菌中的细菌缺少P链。蜡状芽孢杆菌PI-PLC的单核细胞增生李斯特氏菌表达对GPI锚定的蛋白质具有很强的活性，可抑制细菌从液泡中逃逸并在细胞间扩散，导致小鼠的毒力大大降低。从蜡状芽孢杆菌PI-PLC中删除Vbβ链消除了其裂解GPI锚定蛋白质的能力，降低了其抑制作用，并增加了其在小鼠中的毒力。这些结果强烈表明，单核细胞增生李斯特氏菌PI-PLC已发展成为缺乏Vbβ链的单核细胞增生李斯特氏菌发病机理的重要决定因素，从而导致对GPI锚定蛋白的活性大大降低。

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