title: Dual functions for cytosolic α-mannosidase (Man2C1): its down-regulation causes mitochondria-dependent apoptosis independently of its α-mannosidase activity.
abstract: 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.
authors.affiliation: Glycometabolome Team, Systems Glycobiology Research Group, RIKEN Max Planck Joint Research Center, RIKEN Global Research Cluster, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Tadashi
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D050260:Carbohydrate Metabolism / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D008361:Mannosidases / Q000096:biosynthesis* / Q000235:genetics; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D051742:Transcription Factor CHOP / Q000096:biosynthesis / Q000235:genetics; D043323:alpha-Mannosidase
chemical_list: C497249:DDIT3 protein, human; D051742:Transcription Factor CHOP; D008361:Mannosidases; C511245:MAN2C1 protein, human; D043323:alpha-Mannosidase