O-mannosylation: The other glycan player of ER quality control

Nowhere else does the cell employ posttranslational protein modifications as extensively as in the endoplasmic reticulum (ER). In fact, such modifications can comprise the bulk of the mass of a mature protein in some cases. The most common modification is glycosylation, with N-linked glycans being the most commonly studied and best understood. However, the covalent modification of serine and threonine side chains with mannose or O-mannosylation has been gaining interest. Part of the attention comes from the realization that O-mannosylation is a conserved process found in most eukaryotes and defects in O-mannosylation can give rise to human disease. Long known to be important structural modification of some endomembrane system proteins, recent findings reveal that it is a common modification of unfolded proteins. For irreversibly misfolded proteins, O-mannosylation can aid in their disposal through ER or lysosomal pathways. The protein O-mannosylation pathway can also play an instrumental role in monitoring the folding of newly synthesized proteins. Proteins that fail to fold efficiently are O-mannosylated to remove them from harmful futile protein folding cycles and prepare them for disposal. Thus, O-mannosylation joins N-linked glycosylation as a major mechanism involved in the folding and quality control of newly synthesized proteins in the ER.