Journal britannique de recherche Libre accès

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Establishment of N-glycan trimming pathway in the endoplasmic reticulum

Satoshi Ninagawa

Proteins misfolded in the endoplasmic reticulum (ER) are recognized, delivered to retrotranslocation channels, dislocated from the ER to the cytosol, and ubiquitinated and degraded by the proteasome: a pathway collectively termed ER-associated degradation (ERAD). In the glycoprotein ERAD (gpERAD) pathway, two-step mannose trimming from Man9GlcNAc2 (M9) produces oligosaccharides with the α1,6-mannose bond exposed, which is recognized by the lectin ERAD component for subsequent disposal In mammals, how nine mannoses are trimmed in the ER had been discussed but unclear, especially concerning the enzymes that conduct the trimming. MAN1B1 (ER mannosidase I) with a mannosidase homology domain (MHD) was a primary candidate for the trimming from M9 to M8B, but it was clearly demonstrated that endogenous MAN1B1 localized in the Golgi (Pan et al., 2011 MBoC), not in the ER. Other candidates were EDEM1, EDEM2 and EDEM3 containing MHD, of which the enzymatic activities were ambiguous. To investigate functions of endogenous EDEM proteins,