Glycometabolome Team, Systems Glycobiology Research Group, RIKEN Max Planck Joint Research Center, RIKEN Global Research Cluster, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
J Biol Chem. 2013 Apr 26;288(17):11887-96. doi: 10.1074/jbc.M112.425702. Epub 2013 Mar 13.
Cytosolic α-mannosidase (Man2C1) trims free oligosaccharides in mammalian cells, and its down-regulation reportedly delays cancer growth by inducing mitotic arrest or apoptosis. However, the mechanism by which Man2C1 down-regulation induces apoptosis is unknown. Here, we demonstrated that silencing of Man2C1 via small hairpin RNAs induced mitochondria-dependent apoptosis in HeLa cells. Expression of CHOP (C/EBP homologous protein), a transcription factor critical to endoplasmic reticulum stress-induced apoptosis, was significantly up-regulated in Man2C1 knockdown cells. However, this enhanced CHOP expression was not caused by endoplasmic reticulum stress. Interestingly, Man2C1 catalytic activity was not required for this regulation of apoptosis; introduction of mutant, enzymatically inactive Man2C1 rescued apoptotic phenotypes of Man2C1 knockdown cells. These results show that Man2C1 has dual functions: one in glycan catabolism and another in apoptotic signaling.
细胞质α-甘露糖苷酶（Man2C1）可修剪哺乳动物细胞中的游离寡糖，据报道，其下调可通过诱导有丝分裂阻滞或细胞凋亡来延缓癌症生长。然而，Man2C1 下调诱导细胞凋亡的机制尚不清楚。在这里，我们证明了通过短发夹 RNA 沉默 Man2C1 可诱导 HeLa 细胞中线粒体依赖性细胞凋亡。在 Man2C1 敲低细胞中，内质网应激诱导凋亡的关键转录因子 CHOP（C/EBP 同源蛋白）的表达显著上调。然而，这种增强的 CHOP 表达不是由内质网应激引起的。有趣的是，Man2C1 的催化活性对于这种凋亡调控不是必需的；引入突变的、无酶活性的 Man2C1 挽救了 Man2C1 敲低细胞的凋亡表型。这些结果表明 Man2C1 具有双重功能：一种是糖代谢，另一种是凋亡信号。
