Glycobiology, 2002, Vol. 12, No. 5 307-317
© 2002 Oxford University Press
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
2 Department of Pharmacology, Univerity of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9041, USA; 3 Department of Biochemistry II, Heinrich-Duker-Weg 12, Gottingen D-37073, Germany; and 4 Glycobiology and Carbohydrate Chemistry Program, Burnham Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA
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.
1 To whom correspondence should be addressed
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