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.
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.
Shang
Jie
J
Department of Pharmacology, Univerity of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9041, USA.
Körner
Christian
C
Freeze
Hudson
H
Lehrman
Mark A
MA
D050260:Carbohydrate Metabolism; D002352:Carrier Proteins / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005347:Fibroblasts / Q000378:metabolism; D006031:Glycosylation; D006360:Heat-Shock Proteins; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D018832:Molecular Chaperones / Q000235:genetics; D009844:Oligosaccharides / Q000737:chemistry*; D011489:Protein Denaturation; D014158:Transcription, Genetic
D002352:Carrier Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D008055:Lipids; D018832:Molecular Chaperones; D009844:Oligosaccharides