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- Title
Deficiency of α-glucosidase I alters glycoprotein glycosylation and lifespan in Caenorhabditis elegans.
- Authors
Katoh, Toshihiko; Takase, Juri; Tani, Yasushi; Amamoto, Ryuta; Aoshima, Naofumi; Tiemeyer, Michael; Yamamoto, Kenji; Ashida, Hisashi
- Abstract
Endoplasmic reticulum (ER) α-glucosidase I is an enzyme that trims the distal α1,2-linked glucose (Glc) residue from the Glc3Man9GlcNAc2 oligosaccharide following its addition to nascent glycoproteins in the initial step of processing. This reaction is critical to the subsequent processing of N-glycans and thus defects in α-glucosidase I gene in human cause congenital disorder of glycosylation (CDG) type IIb. We identified the Caenorhabditis elegans α-glucosidase I gene (F13H10.4, designated agl-1) that encodes a polypeptide with 36% identity to human α-glucosidase I. The agl-1 cDNA restored the expression of complex-type N-glycans on the cell surface of α-glucosidase I-defective Chinese hamster ovary Lec23 cells. RNAi knockdown of agl-1 [agl-1(RNAi)] produced worms that were visibly similar to wild-type, but lifespan was reduced to about half of the control. Analyses of N-glycosylation in agl-1(RNAi) animals by western blotting and mass spectrometry showed reduction of paucimannose and complex-type glycans and dramatic increase of glucosylated oligomannose glycans. In addition, a significant amount of unusual terminally fucosylated N-glycans were found in agl-1(RNAi) animals. ER stress response was also provoked, leading to the accumulation of large amounts of triglucosylated free oligosaccharides (FOSs) (Glc3Man4–5GlcNAc1–2) in agl-1(RNAi) animals. Acceleration of ER-associated degradation in response to the accumulation of unfolded glycoproteins and insufficient interaction with calnexin/calreticulin in the ER lumen likely accounts for the increase of FOSs. Taken together, these studies in C. elegans demonstrate that decreased ER α-glucosidase I affects the entire N-glycan profile and induces chronic ER stress, which may contribute to the pathophysiology of CDG-IIb in humans.
- Subjects
GLUCOSIDASES; GLYCOPROTEINS; GLYCOSYLATION; CAENORHABDITIS elegans; ENDOPLASMIC reticulum; OLIGOSACCHARIDES; CONGENITAL disorders
- Publication
Glycobiology, 2013, Vol 23, Issue 10, p1142
- ISSN
0959-6658
- Publication type
Article
- DOI
10.1093/glycob/cwt051