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Differential role of FL-BID and t-BID during verotoxin-1-induced apoptosis in Burkitt's lymphoma cells.
Oncogene ( IF 8 ) Pub Date : 2018-May-01 , DOI: 10.1038/s41388-018-0123-5
Justine Debernardi , Emilie Hollville , Marc Lipinski , Joëlle Wiels , Aude Robert

The globotriaosylceramide Gb3 is a glycosphingolipid expressed on a subpopulation of germinal center B lymphocytes which has been recognized as the B cell differentiation antigen CD77. Among tumoral cell types, Gb3/CD77 is strongly expressed in Burkitt's lymphoma (BL) cells as well as other solid tumors including breast, testicular and ovarian carcinomas. One known ligand of Gb3/CD77 is Verotoxin-1 (VT-1), a Shiga toxin produced in specific E. coli strains. Previously, we have reported that in BL cells, VT-1 induces apoptosis via a caspase-dependent and mitochondria-dependent pathway. Yet, the respective roles of various apoptogenic factors remained to be deciphered. Here, this apoptotic pathway was found to require cleavage of the BID protein by caspase-8 as well as activation of two other apoptogenic proteins, BAK and BAX. Surprisingly however, t-BID, the truncated form of BID resulting from caspase-8 cleavage, played no role in the conformational changes of BAK and BAX. Rather, their activation occurred under the control of full length BID (FL-BID). Indeed, introducing a non-cleavable form of BID (BID-D59A) into BID-deficient BL cells restored BAK and BAX activation following VT-1 treatment. Still, t-BID was involved along with FL-BID in the BAK-dependent and BAX-dependent cytosolic release of CYT C and SMAC/DIABLO from the mitochondrial intermembrane space: FL-BID was found to control the homo-oligomerization of both BAK and BAX, likely contributing to the initial release of CYT C and SMAC/DIABLO, while t-BID was needed for their hetero-oligomerization and ensuing release amplification. Together, our results reveal a functional cooperation between BAK and BAX during VT-1-induced apoptosis and, unexpectedly, that activation of caspase-8 and production of t-BID were not mandatory for initiation of the cell death process.

中文翻译:

FL-BID和t-BID在Verkit-1诱导的伯基特淋巴瘤细胞凋亡中的差异作用。

球果糖基神经酰胺Gb3是在生发中心B淋巴细胞的亚群上表达的糖鞘脂,其已被公认是B细胞分化抗原CD77。在肿瘤细胞类型中,Gb3 / CD77在伯基特氏淋巴瘤(BL)细胞以及其他实体瘤(包括乳腺癌,睾丸癌和卵巢癌)中强烈表达。Gb3 / CD77的一种已知配体是Verotoxin-1(VT-1),一种在特定大肠杆菌菌株中产生的志贺毒素。以前,我们已经报道过,在BL细胞中,VT-1通过caspase依赖性和线粒体依赖性途径诱导凋亡。然而,各种细胞凋亡因子的各自作用仍有待研究。在这里,发现该凋亡途径需要通过caspase-8裂解BID蛋白以及激活另外两种凋亡蛋白BAK和BAX。然而,令人惊讶的是,t-BID(由caspase-8裂解产生的截短形式的BID)在BAK和BAX的构象变化中不起作用。而是,它们的激活发生在全长BID(FL-BID)的控制下。实际上,将BID(BID-D59A)的不可裂解形式引入BID缺失的BL细胞中,可在VT-1处理后恢复BAK和BAX的激活。仍然,t-BID与FL-BID一起参与了线粒体膜间空间中CYT C和SMAC / DIABLO的BAK依赖和BAX依赖的胞质释放:发现FL-BID控制着两个BAK的均聚BAX和BAX可能有助于CYT C和SMAC / DIABLO的初始释放,而t-BID则需要它们的异源寡聚化和随后的释放放大。一起,
更新日期:2018-02-14
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