Extension of lipid-linked oligosaccharides is a high-priority aspect of the unfolded protein response: endoplasmic reticulum stress in Type I congenital disorder of glycosylation fibroblasts.

Abstract

Asparagine (N)-linked glycans on endoplasmic reticulum (ER) glycoproteins have critical roles in multiple facets of protein folding and quality control. Inhibition of synthesis of lipid-linked oligosaccharides (LLOs), the precursors of N-linked glycans, causes glycoprotein misfolding. This results in ER stress and triggers the unfolded protein response (UPR), which consists of a set of adaptive events, or "aspects," including enhanced extension of LLO intermediates. Type I congenital disorders of glycosylation (CDGs) are characterized by diminished LLO synthesis and aberrant N-glycosylation. Such defects would be predicted to cause chronic ER stress with continuous UPR activation. We employed a quantitative pharmacological approach with dermal fibroblasts to show that (1) compared with three other well-known UPR aspects (transcriptional activation, inhibition of translation, and cell death), LLO extension was the most sensitive to ER stress; and (2) Type I CDG cells had a mild form of chronic ER stress in which LLO extension was continuously stress-activated, but other aspects of the UPR were unchanged. To our knowledge, Type I CDGs are the only human diseases shown to have chronic ER stress resulting from genetic defects in the ER quality control system. In conclusion, LLO extension has a high priority in the UPR of dermal fibroblasts. This suggests that cells stimulate N-glycosylation as part of a first line of defense against ER dysfunction. The broader implications of these results for the biological significance of the UPR are discussed.

• Authors: Jie Shang, Christian Körner, Hudson Freeze, Mark A Lehrman
• Journal: Glycobiology (Glycobiology) Vol. 12 Issue 5 Pg. 307-17 (May 2002) ISSN: 0959-6658 [Print] England
• PMID: 12070073 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Carrier Proteins
• Endoplasmic Reticulum Chaperone BiP
• Heat-Shock Proteins
• Lipids
• Molecular Chaperones
• Oligosaccharides

Topics

• Carbohydrate Metabolism
• Carrier Proteins (genetics)
• Endoplasmic Reticulum (metabolism)
• Endoplasmic Reticulum Chaperone BiP
• Fibroblasts (metabolism)
• Glycosylation
• Heat-Shock Proteins
• Humans
• Lipids (chemistry)
• Molecular Chaperones (genetics)
• Oligosaccharides (chemistry)
• Protein Denaturation
• Transcription, Genetic