Glycosylation is crucial for the folding and function of many proteins. How the cell deals with a lapse in glycosylation was unknown. Shang et al. (page 605) now show that a reduction in available glycans prompts an ER stress protein called PERK to put protein synthesis in a lower gear, allowing the glycan resource to restock.

Glycans are transferred to new peptides in the ER from a lipid-linked oligosaccharide (LLO). This LLO pool is often defective in patients who have congenital glycosylation disorders. Shang et al. mimicked these defects by culturing mammalian cells in low glucose medium. One LLO molecule normally has 14 sugars available for transfer to peptides, but low glucose dropped the number to as few as four.

This sugar defect, the group finds, can be fixed by limiting translation. An ER stress response factor called PERK senses the glycosylation problems via the accumulation of incorrectly folded proteins and reduces the activity of a translation initiation factor called eIF2α.

The team showed that PERK's ability to slow down translation reduced the demand on the glycosylation machinery, which in turn allowed more time for the biosynthesis of LLO forms carrying the correct quota of sugars.