Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes
Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes
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DOI：
10.1038/ncb1192
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发表时间：
2004-12-01
影响因子：
21.3
通讯作者：
Tsujimoto, Y
中科院分区：
文献类型：
--
作者：
Shimizu, S;Kanaseki, T;Tsujimoto, Y
程序性细胞死亡可分为几类，包括I型（凋亡）和II型（自噬性死亡）（1，2）。Bcl-2蛋白家族是细胞凋亡的充分表征的调节剂（3），并且该家族的多结构域促细胞凋亡成员，如Bax和巴克，充当线粒体网关，在此多种细胞凋亡信号会聚（4-6）。尽管来自Bax/巴克双敲除小鼠的胚胎成纤维细胞对凋亡具有抗性（4-6），我们发现这些细胞在死亡刺激后仍然经历非凋亡性死亡。电子显微镜和生化研究表明，双敲除细胞死亡与自噬体/自溶酶体。双敲除细胞的这种非凋亡性死亡被自噬抑制剂（包括3-甲基腺嘌呤）抑制，依赖于自噬蛋白APG 5和Beclin 1（能够结合Bcl-2/Bcl-x（L）），并且还被Bcl-x（L）调节。这些结果表明，Bcl-2蛋白家族不仅调节细胞凋亡，而且还控制依赖于自噬基因的非凋亡程序性细胞死亡。
Programmed cell death can be divided into several categories including type I (apoptosis) and type II (autophagic death)(1,2). The Bcl-2 family of proteins are well-characterized regulators of apoptosis(3), and the multidomain pro-apoptotic members of this family, such as Bax and Bak, act as a mitochondrial gateway where a variety of apoptotic signals converge(4-6). Although embryonic fibroblasts from Bax/Bak double knockout mice are resistant to apoptosis(4-6), we found that these cells still underwent a non-apoptotic death after death stimulation. Electron microscopic and biochemical studies revealed that double knockout cell death was associated with autophagosomes/autolysosomes. This non-apoptotic death of double knockout cells was suppressed by inhibitors of autophagy, including 3-methyl adenine, was dependent on autophagic proteins APG5 and Beclin 1 (capable of binding to Bcl-2/Bcl-x(L)), and was also modulated by Bcl-x(L). These results indicate that the Bcl-2 family of proteins not only regulates apoptosis, but also controls non-apoptotic programmed cell death that depends on the autophagy genes.