Acidic sphingomyelinase (ASM) is necessary for fas-induced GD3 ganglioside accumulation and efficient apoptosis of lymphoid cells.
Acidic sphingomyelinase (ASM) is necessary for fas-induced GD3 ganglioside accumulation and efficient apoptosis of lymphoid cells.
复制标题
酸性鞘磷脂酶（ASM）对于FAS诱导的GD3神经节苷脂的积累和淋巴样细胞有效凋亡是必需的。
DOI：
10.1084/jem.187.6.897
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发表时间：
1998-03-16
影响因子：
15.3
通讯作者：
Testi, R
中科院分区：
文献类型：
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作者：
De Maria, R;Rippo, M R;Schuchman, E H;Testi, R
鞘磷脂水解产生的神经酰胺是Fas（APO-1/CD 95）介导的凋亡信号的重要介质。然而，单个鞘磷脂酶所起作用的确切证据仍然缺乏。我们分析了来自尼曼匹克病（NPD）患者的淋巴母细胞样细胞系，NPD是一种常染色体隐性遗传疾病，由酸性鞘磷脂酶（ASM）基因内的功能缺失突变引起。NPD淋巴母细胞，显示正常的中性鞘磷脂酶活性，不能激活ASM响应Fas交联，不像正常的淋巴母细胞。NPD成淋巴细胞也不能积累神经酰胺诱导的细胞死亡的下游介质GD 3神经节苷脂（De Maria，R.，L. Lenti，F. Malisan，F.达戈斯蒂诺，B。Tomassini，A. Zeuner，M.R.里波河泰斯蒂1997.科学277：1652-1655），并且在Fas交联后显示出基本上无效的凋亡。低效的细胞凋亡是由于缺乏ASM活性，因为NPD淋巴母细胞中来自Fas的近端信号传导未受损，并且细胞凋亡可以通过用外源性神经酰胺传递ASM缺陷而有效地触发。此外，甘露糖受体介导的ASM转移到NPD淋巴母细胞拯救他们的能力，瞬时激活ASM，积累GD 3，并迅速进行凋亡后Fas交联。这些结果提供了明确的遗传学证据ASM的作用，从Fas的凋亡信号的进展。
Ceramides deriving from sphingomyelin hydrolysis are important mediators of apoptotic signals originating from Fas (APO-1/CD95). However, definitive evidence for the role played by individual sphingomyelinases is still lacking. We have analyzed lymphoblastoid cell lines derived from patients affected by Niemann Pick disease (NPD), an autosomal recessive disorder caused by loss-of-function mutations within the acidic sphingomyelinase (ASM) gene. NPD lymphoblasts, which display normal neutral sphingomyelinase activity, fail to activate ASM in response to Fas cross-linking, unlike normal lymphoblasts. NPD lymphoblasts also fail to accumulate GD3 ganglioside, a downstream mediator of ceramide-induced cell death (De Maria, R., L. Lenti, F. Malisan, F. D'Agostino, B. Tomassini, A. Zeuner, M.R. Rippo, R. Testi. 1997. Science. 277:1652–1655), and display a substantially inefficient apoptosis after Fas cross-linking. Inefficient apoptosis is due to lack of ASM activity, because proximal signaling from Fas in NPD lymphoblasts is not impaired and apoptosis can be efficiently triggered by passing the ASM defect with exogenous ceramides. Moreover, mannose receptor–mediated transfer of ASM into NPD lymphoblasts rescues their ability to transiently activate ASM, accumulate GD3, and rapidly undergo apoptosis after Fas cross-linking. These results provide definitive genetic evidence for the role of ASM in the progression of apoptotic signals originating from Fas.