Endoplasmic reticulum-associated degradation of mammalian glycoproteins involves sugar chain trimming to Man6-5GlcNAc2.
Endoplasmic reticulum-associated degradation of misfolded or misprocessed glycoproteins in mammalian cells is prevented by inhibitors of class I alpha-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 Man5GlcNAc2. 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.
Frenkel
Zehavit
Z
Department of Cell Research and Immunology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
Gregory
Walter
W
Kornfeld
Stuart
S
Lederkremer
Gerardo Z
GZ
D016475:3T3 Cells; D000818:Animals; D019556:COS Cells; D037281:Calnexin / Q000737:chemistry; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005947:Glucose / Q000737:chemistry; D005964:Glucosyltransferases / Q000737:chemistry; D006023:Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D006031:Glycosylation; D008358:Mannose / Q000737:chemistry*; D051379:Mice; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D008956:Models, Chemical; D009097:Multienzyme Complexes / Q000378:metabolism; D009154:Mutation; D009844:Oligosaccharides / Q000737:chemistry*; D011233:Precipitin Tests; D046988:Proteasome Endopeptidase Complex; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D013997:Time Factors
D006023:Glycoproteins; D009097:Multienzyme Complexes; D009844:Oligosaccharides; C477742:mannosyl(6)-N-acetyl(2)glucose; D037281:Calnexin; C058642:mannosyl(5)-N-acetyl(2)-glucose; D005964:Glucosyltransferases; C072423:mannosylglycoprotein 1,3-glucosyltransferase; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D005947:Glucose; D008358:Mannose