A sweet send-off

Abstract

One-third of all proteins encoded by the human genome enter the cellular secretory pathway. The first compartment, the endoplasmic reticulum (ER), is specialized for protein folding, where newly synthesized polypeptides are guided by chaperones and folding enzymes to assume a final native state. Quality control is imposed when this process fails—misfolded proteins are retained in the ER and eventually degraded, thereby keeping the cell healthy and free of protein “traffic jams.” For proteins that are glycosylated, triage decisions (and their timing) involve mannosidases and mannose-specific lectins that recognize an N-linked glycan (N-linked glycosylation site in which a nitrogen atom has been attached to an amino acid) on the polypeptide chain (1). On page 978 of this issue, Xu et al. (2) find that the folding of nonglycosylated proteins is terminated by a similar triage mechanism that surprisingly involves a mannose residue. This “O-mannosylation” (a sugar molecule is added to an oxygen atom in serine or threonine) may act as a cell's timer to stop the lingering of nonglycosylated proteins that simply take too long to fold and remove them from the secretory pathway.