Figure 3. N-linked glycans as protein sorting tags.

N-linked glycans are synthesized by Alg genes and transferred to polypeptides by oligosaccharyltransferase (OST) to asparagine residues in the Asn-Xxx-Ser/Thr sequon. OST exists as two isoforms that differ in their catalytic subunits, STT3A and STT3B. Glucosidase I and II remove the first two glucose moieties (blue spheres), generating a monoglucosylated glycoform, which enables the glycoprotein to enter the lectin folding cycle by engaging calnexin (CNX) and calreticulin (CRT)¹¹. Removal of the remaining glucose by glucosidase II releases the protein from CNX/CRT. If the glycoprotein requires additional folding cycles, a glucose moiety is added by UGT1 and the protein re-engages CNX and CRT. Proteins that have reached their native states (cube) are demannosylated by ER mannosidase I (ERManI). The mannose-trimmed glycans are recognized by ERGIC-53, VIPL and VIP36, which facilitate their packaging into Golgi-bound vesicles⁵². Proteins that do not fold into their native states undergo extensive mannose trimming by the mannosidase-like proteins EDEM1-3. Glycoforms generated by EDEM1-3 are recognized by the ERAD lectin receptors OS-9 and XTP3-B, which bring the misfolded proteins to the ERAD complex. The relative transcript levels of some of the proteins involved in glycoproteostasis are upregulated by UPR activation (highlighted in yellow)⁷². A number of enzyme inhibitors (red) have been employed to study the effects of glycan processing on protein trafficking and degradation.