Metabolically programmed quality control system for dolichol-linked oligosaccharides.
The glycolipid Glc3Man9GlcNAc2-pyrophosphate-dolichol serves as the precursor for asparagine (N)-linked protein glycosylation in mammals. The biosynthesis of dolichol-linked oligosaccharides (DLOs) is arrested in low-glucose environments via unknown mechanisms, resulting in abnormal N-glycosylation. Here, we show that under glucose deprivation, DLOs are prematurely degraded during the early stages of DLO biosynthesis by pyrophosphatase, leading to the release of singly phosphorylated oligosaccharides into the cytosol. We identified that the level of GDP-mannose (Man), which serves as a donor substrate for DLO biosynthesis, is substantially reduced under glucose deprivation. We provide evidence that the selective shutdown of the GDP-Man biosynthetic pathway is sufficient to induce the release of phosphorylated oligosaccharides. These results indicate that glucose-regulated metabolic changes in the GDP-Man biosynthetic pathway cause the biosynthetic arrest of DLOs and facilitate their premature degradation by pyrophosphatase. We propose that this degradation system may avoid abnormal N-glycosylation with premature oligosaccharides under conditions that impair efficient DLO biosynthesis.
Glycometabolome Team, Systems Glycobiology Research Group and Disease Glycomics Team, Systems Glycobiology Research Group, RIKEN-Max Planck Joint Research Center, Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Yoichiro
Y
Harada
Kazuki
K
Nakajima
Yuki
Y
Masahara-Negishi
Hudson H
HH
Freeze
Takashi
T
Angata
Naoyuki
N
Taniguchi
Tadashi
T
Suzuki
D000818:Animals; D001216:Asparagine / Q000378:metabolism*; D053898:Biosynthetic Pathways / Q000502:physiology*; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000378:metabolism; D004286:Dolichols / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005347:Fibroblasts; D005947:Glucose / Q000172:deficiency; D006031:Glycosylation; D006155:Guanosine Diphosphate Mannose / Q000096:biosynthesis*; D051379:Mice; D008954:Models, Biological; D009844:Oligosaccharides / Q000096:biosynthesis* / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D011134:Polysaccharides / Q000378:metabolism; D011755:Pyrophosphatases / Q000378:metabolism; D053719:Tandem Mass Spectrometry
D004286:Dolichols; D009844:Oligosaccharides; D010455:Peptides; D011134:Polysaccharides; D006155:Guanosine Diphosphate Mannose; D001216:Asparagine; D011755:Pyrophosphatases; D005947:Glucose