Granulysin-induced apoptosis. I. Involvement of at least two distinct pathways.
Granulysin-induced apoptosis. I. Involvement of at least two distinct pathways.
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DOI：
10.4049/jimmunol.161.4.1758
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发表时间：
1998-08
影响因子：
4.4
通讯作者：
Susana Gamen;Dennis A. Hanson;Allan A. Kaspar;Javier Naval;A. Krensky;A. Anel
中科院分区：
文献类型：
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作者：
Susana Gamen;Dennis A. Hanson;Allan A. Kaspar;Javier Naval;A. Krensky;A. Anel
颗粒溶素是新近发现的一种由CTL和NK细胞通过颗粒介导的胞吐作用释放的细胞溶解分子。它与鞘脂激活蛋白样蛋白（包括NK-溶素和变形虫）具有同源性，并与肿瘤细胞和微生物的裂解有关。在本研究中，我们表明，重组颗粒溶解素单独诱导Jurkat细胞凋亡。这种细胞凋亡与神经酰胺/鞘磷脂比率增加6倍有关，暗示鞘磷脂酶的激活。颗粒溶素和神经酰胺诱导的细胞凋亡是相似的，因为它们都仅被更有选择性的半胱氨酸蛋白酶p32（半胱天冬酶3）样半胱天冬酶抑制剂N-乙酰基-Asp-Glu-Val-Asp醛最低限度地抑制，而它们被更通用的半胱天冬酶抑制剂苄氧基羰基-Val-Ala-Asp-氟甲基酮（Z-VAD-fatomethyl）显著抑制。然而，虽然Z-VAD-fmk几乎完全抑制神经酰胺诱导的细胞凋亡，但使用颗粒溶解素观察到Z-VAD-fmk抗性组分。颗粒溶素也可通过神经酰胺合成酶抑制剂伏马菌素B1的长期处理导致鞘磷脂耗竭的细胞凋亡。这些数据表明，颗粒溶解素诱导靶细胞死亡的神经酰胺和半胱天冬酶依赖性和非依赖性途径。
Granulysin is a newly described cytolytic molecule released by CTL and NK cells via granule-mediated exocytosis. It shares homology with saposin-like proteins, including NK-lysin and amoebapores, and has been implicated in the lysis of tumor cells and microbes. In the present study we show that recombinant granulysin alone induces apoptosis of Jurkat cells. This apoptosis is associated with a sixfold increase in the ceramide/sphingomyelin ratio, implicating the activation of sphingomyelinases. Granulysin- and ceramide-induced apoptosis are similar in that they both are only minimally inhibited by the more selective cysteine protease p32 (caspase 3)-like caspase inhibitor N-acetyl-Asp-Glu-Val-Asp aldehyde, while they are significantly inhibited by the more general caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-fmk). Nevertheless, while Z-VAD-fmk almost completely inhibits ceramide-induced apoptosis, a Z-VAD-fmk-resistant component was observed using granulysin. Granulysin also causes apoptosis in cells depleted of sphingomyelin by prolonged treatment with the ceramide synthase inhibitor fumonisin B1. These data indicate that granulysin induces target cell death by both ceramide- and caspase-dependent and -independent pathways.