UGGT1/2-mediated reglucosylation ofN-glycan competes with ER-associated degradation of unstable and misfolded glycoproteins

Abstract

ABSTRACTHere we investigated how the fate (folding versus degradation) of glycoproteins is determined in the endoplasmic reticulum (ER). Monoglucosylated glycoproteins are recognized by lectin chaperones to facilitate their folding, whereas glycoproteins with well-trimmed mannoses are subjected to glycoprotein ER-associated degradation (gpERAD). Previously we elucidated how mannoses are trimmed by EDEM family members (George et al., 2020, 2021 eLife). Though reglucosylation by UGGTs (UGGT1 and UGGT2) was reported to have no effect on substrate degradation, here, we directly test this using genetically disrupted UGGTs. Strikingly, the results showed that UGGTs (mainly UGGT1) delayed the degradation of misfolded substrates and unstable glycoproteins including ATF6α. An experiment with a point mutant of UGGT1 indicated that the glucosylation activity of UGGT was required for the inhibition of early glycoprotein degradation. We further demonstrated the physiological importance of UGGT, since ATF6 cannot function properly without UGGTs. The fate of glycoproteins is determined by a tug-of-war between structure formation by UGGTs and degradation by EDEMs. Thus, our work strongly suggests that UGGTs are central factors in ER protein quality control via regulation of both glycoprotein folding and degradation.