N‐glycosylation mediated folding and quality control in serine proteases of the hepsin family

Abstract

N‐linked glycans are specifically attached to asparagine residues in a N‐X‐S/T motif of secretory pathway glycoproteins. N‐glycosylation of newly synthesized glycoproteins directs their folding via the lectin chaperones calnexin and calreticulin that are associated with protein‐folding enzymes and glycosidases of the endoplasmic reticulum (ER). Misfolded glycoproteins are retained in the ER by the same lectin chaperones. The work by Sun et al. (FEBS J 2023, 10.1111/febs.16757) in this issue focusses on hepsin, a serine protease on the surface of liver and other organs. The authors deduce that spatial positioning of N‐glycans on one side of a conserved domain of hepsin, known as the scavenger receptor‐rich cysteine domain, regulates calnexin selection for hepsin maturation and transport through the secretory pathway. If N‐glycosylation is elsewhere on hepsin, then it is misfolded and has a prolonged accumulation with calnexin and BiP. This association coincides with the engagement of stress response pathways that sense glycoprotein misfolding. The topological considerations of N‐glycosylation dissected by Sun et al. may help unravel how key sites of N‐glycosylation sites required for protein folding and transport have evolved to select the lectin chaperone calnexin pathway for folding and quality control.