Translation attenuation by PERK balances ER glycoprotein synthesis with lipid-linked oligosaccharide flux

Jie Shang, Ningguo Gao, Randal J. Kaufman, David Ron, Heather P. Harding, Mark A. Lehrman

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Endoplasmic reticulum (ER) homeostasis requires transfer and subsequent processing of the glycan Glc3Man9GlcNAc2 (G3M9Gn2) from the lipid-linked oligosaccharide (LLO) glucose3mannose9N-acetylglucosamine 2-P-P-dolichol (G3M9Gn2-P-P-Dol) to asparaginyl residues of nascent glycoprotein precursor polypeptides. However, it is unclear how the ER is protected against dysfunction from abnormal accumulation of LLO intermediates and aberrant N-glycosylation, as occurs in certain metabolic diseases. In metazoans phosphorylation of eukaryotic initiation factor 2α (eIF2α) on Ser51 by PERK (PKR-like ER kinase), which is activated by ER stress, attenuates translation initiation. We use brief glucose deprivation to simulate LLO biosynthesis disorders, and show that attenuation of polypeptide synthesis by PERK promotes extension of LLO intermediates to G3M9Gn2-P-P-Dol under these substrate-limiting conditions, as well as counteract abnormal N-glycosylation. This simple mechanism requires eIF2α Ser51 phosphorylation by PERK, and is mimicked by agents that stimulate cytoplasmic stress-responsive Ser51 kinase activity. Thus, by sensing ER stress from defective glycosylation, PERK can restore ER homeostasis by balancing polypeptide synthesis with flux through the LLO pathway.

Original languageEnglish (US)
Pages (from-to)605-616
Number of pages12
JournalJournal of Cell Biology
Volume176
Issue number5
DOIs
StatePublished - Feb 26 2007

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Endoplasmic Reticulum
Glycoproteins
Phosphotransferases
Eukaryotic Initiation Factor-2
Glycosylation
Endoplasmic Reticulum Stress
Peptides
Homeostasis
Phosphorylation
Dolichol
Acetylglucosamine
Metabolic Diseases
Polysaccharides
lipid-linked oligosaccharides
Glucose

ASJC Scopus subject areas

  • Cell Biology

Cite this

Translation attenuation by PERK balances ER glycoprotein synthesis with lipid-linked oligosaccharide flux. / Shang, Jie; Gao, Ningguo; Kaufman, Randal J.; Ron, David; Harding, Heather P.; Lehrman, Mark A.

In: Journal of Cell Biology, Vol. 176, No. 5, 26.02.2007, p. 605-616.

Research output: Contribution to journalArticle

Shang, Jie ; Gao, Ningguo ; Kaufman, Randal J. ; Ron, David ; Harding, Heather P. ; Lehrman, Mark A. / Translation attenuation by PERK balances ER glycoprotein synthesis with lipid-linked oligosaccharide flux. In: Journal of Cell Biology. 2007 ; Vol. 176, No. 5. pp. 605-616.
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