Published online
doi:10.1083/jcb.200607007
The Journal of Cell Biology, Vol. 176, No. 5, 605-616
The Rockefeller University Press, 0021-9525 $30.00
© Shang et al.
Translation attenuation by PERK balances ER glycoprotein synthesis with lipid-linked oligosaccharide flux
Jie Shang1,
Ningguo Gao1,
Randal J. Kaufman2,
David Ron3,4,5,
Heather P. Harding3,6, and
Mark A. Lehrman1
1 Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390
2 Howard Hughes Medical Institute and Departments of Internal Medicine and Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109
3 Skirball Institute, 4 Department of Medicine, 5 Department of Cell Biology, and 6 Department of Pharmacology, New York University School of Medicine, New York, NY 10016
Correspondence to Mark A. Lehrman: mark.lehrman{at}utsouthwestern.edu
Endoplasmic reticulum (ER) homeostasis requires transfer and subsequent processing of the glycan Glc3Man9GlcNAc2 (G3M9Gn2) from the lipid-linked oligosaccharide (LLO) glucose3mannose9N-acetylglucosamine2-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 2
(eIF2) 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 eIF2 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.
Abbreviations used in this paper: ANDS, 7-amino-1,3-naphthalenedisulfonic acid; ARS, arsenite; CDG, congenital disorders of glycosylation; CHX, cycloheximide; DIA, diamide; DIS, disulfiram; Dol, dolichol; DTT, dithiothreitol; eIF, eukaryotic initiation factor; FACE, fluorophore-assisted carbohydrate electrophoresis; G3M9Gn2-P-P-Dol, glucose3mannose9N-acetylglucosamine2-P-P-dolichol; LLO, lipid-linked oligosaccharide; MEF, mouse embryonic fibroblast; OT, oligosaccharyltransferase; PERK, PKR-like ER kinase; TG, thapsigargin; UPR, unfolded protein response.
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