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Metabolically programmed quality control system for dolichol-linked oligosaccharides.

Yoichiro Harada1, Kazuki Nakajima, Yuki Masahara-Negishi

  • 1Glycometabolome 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.

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Summary
This summary is machine-generated.

Under glucose deprivation, dolichol-linked oligosaccharide (DLO) biosynthesis halts. This study reveals premature DLO degradation by pyrophosphatase, preventing abnormal N-glycosylation.

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Area of Science:

  • Biochemistry
  • Cell Biology
  • Glycobiology

Background:

  • Asparagine (N)-linked protein glycosylation is crucial for protein function in mammals.
  • The precursor for N-linked glycosylation is Glc3Man9GlcNAc2-pyrophosphate-dolichol.
  • Dolichol-linked oligosaccharide (DLO) biosynthesis is known to arrest under low-glucose conditions through unknown mechanisms, leading to aberrant N-glycosylation.

Purpose of the Study:

  • To elucidate the mechanisms underlying the arrest of DLO biosynthesis in low-glucose environments.
  • To identify the factors responsible for premature DLO degradation.
  • To understand how cells prevent abnormal N-glycosylation during glucose deprivation.

Main Methods:

  • Investigating DLO degradation pathways under glucose deprivation.
  • Measuring GDP-mannose (Man) levels during glucose starvation.
  • Analyzing the impact of the GDP-Man biosynthetic pathway on DLO stability.

Main Results:

  • Under glucose deprivation, DLOs are prematurely degraded by pyrophosphatase during early biosynthesis.
  • This degradation releases singly phosphorylated oligosaccharides into the cytosol.
  • Glucose deprivation significantly reduces GDP-mannose levels, a key substrate for DLO synthesis.
  • Selective shutdown of the GDP-mannose biosynthetic pathway is sufficient to trigger phosphorylated oligosaccharide release.

Conclusions:

  • Glucose-regulated metabolic changes in the GDP-mannose pathway arrest DLO biosynthesis.
  • Premature DLO degradation by pyrophosphatase prevents abnormal N-glycosylation when DLO biosynthesis is impaired.
  • This degradation system acts as a protective mechanism against aberrant glycosylation under metabolic stress.