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

Jie Shang, Christian Körner, Hudson Freeze, Mark A. Lehrman

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39 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)307-317
Number of pages11
JournalGlycobiology
Volume12
Issue number5
StatePublished - 2002

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Glycosylation
Unfolded Protein Response
Endoplasmic Reticulum Stress
Fibroblasts
Congenital Disorders of Glycosylation
Endoplasmic Reticulum
Proteins
Quality Control
Quality control
Polysaccharides
Glycoproteins
Chemical activation
Protein folding
Skin
Defects
Asparagine
Protein Folding
Cell death
Transcriptional Activation
Type In Congenital Disorder of Glycosylation

Keywords

  • Congenital disorder of glycosylation
  • Endoplasmic reticulum stress
  • Glycosylation
  • Lipid-linked oligosaccharide
  • Unfolded protein response

ASJC Scopus subject areas

  • Biochemistry

Cite this

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title = "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.",
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T1 - Extension of lipid-linked oligosaccharides is a high-priority aspect of the unfolded protein response

T2 - Endoplasmic reticulum stress in Type I congenital disorder of glycosylation fibroblasts

AU - Shang, Jie

AU - Körner, Christian

AU - Freeze, Hudson

AU - Lehrman, Mark A.

PY - 2002

Y1 - 2002

N2 - 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.

AB - 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.

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