O-GlcNAcylation, which is the modification of protein serine or threonine residues with the sugar N-acetylglucosamine (GlcNAc), plays a key role in cell physiology. But the mechanisms by which it acts are not completely understood. Yanping Zhu, David J. Vocadlo, and coworkers at Canada’s Simon Fraser University now report that O-GlcNAcylation occurs at higher levels cotranslationally—that is, while proteins are being synthesized on the ribosome—than posttranslationally (Nat. Chem. Biol. 2015, DOI: 10.1038/nchembio.1774). They also find that O-GlcNAcylation inhibits ubiquitination of nascent proteins, a modification that would otherwise mark them for disposal. Inhibiting ubiquitination thus stabilizes proteins and aids proteostasis, the maintenance of proper levels of functional proteins in cells. Vocadlo notes that his group hopes to learn more about the molecular mechanism by which O-GlcNAc decreases ubiquitination on the nascent chains.