Mechanisms of productive folding and endoplasmic reticulum-associated degradation of glycoproteins and non-glycoproteins

Background: The quality of proteins destined for the secretory pathway is ensured by two distinct mechanisms in the endoplasmic reticulum (ER): productive folding of newly synthesized proteins, which is assisted by ER-localized molecular chaperones and in most cases also by disulfide bond formation and transfer of an oligosaccharide unit; and ER-associated degradation (ERAD), in which proteins unfolded or misfolded in the ER are recognized and processed for delivery to the ER membrane complex, retrotranslocated through the complex with simultaneous ubiquitination, extracted by AAA-ATPase to the cytosol, and finally degraded by the proteasome. Scope of review: We describe the mechanisms of productive folding and ERAD, with particular attention to glycoproteins versus non-glycoproteins, and to yeast versus mammalian systems. Major conclusion: Molecular mechanisms of the productive folding of glycoproteins and non-glycoproteins mediated by molecular chaperones and protein disulfide isomerases are well conserved from yeast to mammals. Additionally, mammals have gained an oligosaccharide structure-dependent folding cycle for glycoproteins. The molecular mechanisms of ERAD are also well conserved from yeast to mammals, but redundant expression of yeast orthologues in mammals has been encountered, particularly for components involved in recognition and processing of glycoproteins and components of the ER membrane complex involved in retro-translocation and simultaneous ubiquitination of glycoproteins and non-glycoproteins. This may reflect an evolutionary consequence of increasing quantity or quality needs toward mammals. General significance: The introduction of innovative genome editing technology into analysis of the mechanisms of mammalian ERAD, as exemplified here, will provide new insights into the pathogenesis of various diseases.

Automated summary

The quality of proteins in the endoplasmic reticulum is ensured by productive folding and ERAD mechanisms, with differences in folding between glycoproteins and non-glycoproteins, as well as between yeast and mammalian systems. The molecular mechanisms of folding and ERAD are conserved across species, reflecting evolutionary consequences and potential insights into disease pathogenesis with the use of innovative genome editing technology.