Protection from Endogenous Perforin: Glycans and the C Terminus Regulate Exocytic Trafficking in Cytotoxic Lymphocytes
Protection from Endogenous Perforin: Glycans and the C Terminus Regulate Exocytic Trafficking in Cytotoxic Lymphocytes
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DOI：
10.1016/j.immuni.2011.04.007
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发表时间：
2011-06-24
期刊：
影响因子：
32.4
通讯作者：
Voskoboinik, Ilia
中科院分区：
文献类型：
--
作者：
Brennan, Amelia J.;Chia, Jenny;Voskoboinik, Ilia
细胞毒性淋巴细胞介导的细胞凋亡依赖于穿孔素向分泌颗粒的传递及其在颗粒胞吐后在靶细胞中形成钙依赖性孔的能力。目前尚不清楚细胞毒性淋巴细胞如何合成和储存穿孔素而不引起损伤或死亡。我们发现穿孔蛋白的极端C端对于从内质网到高尔基室的快速运输至关重要。c端色氨酸残基的取代导致内质网中穿孔素的保留，随后是钙依赖性毒性活性，消除宿主细胞。我们还发现穿孔素的n链糖基化对于从高尔基体转运到分泌颗粒至关重要。总的来说，完整的C端和n链糖基化提供了穿孔素从内质网到分泌颗粒的准确和有效的出口，对细胞毒性淋巴细胞的存活至关重要。
Cytotoxic lymphocyte-mediated apoptosis is dependent on the delivery of perforin to secretory granules and its ability to form calcium-dependent pores in the target cell after granule exocytosis. It is unclear how cytotoxic lymphocytes synthesize and store perforin without incurring damage or death. We discovered that the extreme C terminus of perforin was essential for rapid trafficking from the endoplasmic reticulum to the Golgi compartment. Substitution of the C-terminal tryptophan residue resulted in retention of perforin in the ER followed by calcium-dependent toxic activity that eliminated host cells. We also found that N-linked glycosylation of perforin was critical for transport from the Golgi to secretory granules. Overall, an intact C terminus and N-linked glycosylation provide accurate and efficient export of perforin from the endoplasmic reticulum to the secretory granules and are critical for cytotoxic lymphocyte survival.