Endoplasmic Reticulum-associated Degradation of Mammalian Glycoproteins Involves Sugar Chain Trimming to Man_6-5GlcNAc₂

Endoplasmic reticulum-associated degradation of misfolded or misprocessed glycoproteins in mammalian cells is prevented by inhibitors of class I α-mannosidases implicating mannose trimming from the precursor oligosaccharide Glc₃Man₉GlcNAc₂ as an essential step in this pathway. However, the extent of mannose removal has not been determined. We show here that glycoproteins subject to endoplasmic reticulum-associated degradation undergo reglucosylation, deglucosylation, and mannose trimming to yield Man₆GlcNAc₂ and Man ₅GlcNAc₂. These structures lack the mannose residue that is the acceptor of glucose transferred by UDP-Glc:glycoprotein glucosyltransferase. This could serve as a mechanism for removal of the glycoproteins from folding attempts catalyzed by cycles of reglucosylation and calnexin/calreticulin binding and result in targeting of these molecules for proteasomal degradation.