Ceramide biogenesis is required for radiation-induced apoptosis in the germ line of C. elegans.
Ceramide biogenesis is required for radiation-induced apoptosis in the germ line of C. elegans.
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DOI：
10.1126/science.1158111
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发表时间：
2008-10-03
期刊：
影响因子：
--
通讯作者：
Kolesnick R
中科院分区：
文献类型：
--
作者：
Deng X;Yin X;Allan R;Lu DD;Maurer CW;Haimovitz-Friedman A;Fuks Z;Shaham S;Kolesnick R
神经酰胺参与细胞凋亡途径一直是一个有争议的话题。为了解决这一争议，我们测试了秀丽隐杆线虫鞘脂代谢保守基因的功能丧失（LF）突变体。虽然体细胞（发育）凋亡不受影响，电离辐射诱导的生殖细胞凋亡的神经酰胺合酶失活后被抹杀，并恢复后显微注射长链天然神经酰胺。辐射诱导的神经酰胺浓度增加定位于线粒体，并且是BH 3结构域蛋白EGL-1介导的CED-4（APAF-1样蛋白）从CED-9（Bcl-2家族成员）/CED-4复合物中置换所需的，CED-3半胱天冬酶活化中的一个专性步骤。这些研究定义了CEP-1（肿瘤抑制基因p53的蠕虫同源物）介导的EGL-1积累和神经酰胺脱氢酶介导的神经酰胺生成，通过平行途径整合在线粒体膜上调节应激诱导的细胞凋亡。
Ceramide engagement in apoptotic pathways has been a topic of controversy. To address this controversy, we tested loss-of-function (lf) mutants of conserved genes of sphingolipid metabolism in Caenorhabditis elegans. Although somatic (developmental) apoptosis was unaffected, ionizing radiation–induced apoptosis of germ cells was obliterated upon inactivation of ceramide synthase and restored upon microinjection of long-chain natural ceramide. Radiation-induced increase in the concentration of ceramide localized to mitochondria and was required for BH3-domain protein EGL-1–mediated displacement of CED-4 (an APAF-1–like protein) from the CED-9 (a Bcl-2 family member)/CED-4 complex, an obligate step in activation of the CED-3 caspase. These studies define CEP-1 (the worm homolog of the tumor suppressor p53)–mediated accumulation of EGL-1 and ceramide synthase–mediated generation of ceramide through parallel pathways that integrate at mitochondrial membranes to regulate stress-induced apoptosis.
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