Glycoprotein quality control in the endoplasmic reticulum. Mannose trimming by endoplasmic reticulum mannosidase I times the proteasomal degradation of unassembled immunoglobulin subunits.
Quality control in the endoplasmic reticulum must discriminate nascent proteins in their folding process from terminally unfolded molecules, selectively degrading the latter. Unassembled Ig-mu and J chains, two glycoproteins with five N-linked glycans and one N-linked glycan, respectively, are degraded by cytosolic proteasomes after a lag from synthesis, during which glycan trimming occurs. Inhibitors of mannosidase I (kifunensine), but not of mannosidase II (swainsonine), prevent the degradation of mu chains. Kifunensine also inhibits J chain dislocation and degradation, without inhibiting secretion of IgM polymers. In contrast, glucosidase inhibitors do not significantly affect the kinetics of mu and J degradation. These results suggest that removal of the terminal mannose from the central branch acts as a timer in dictating the degradation of transport-incompetent, glycosylated Ig subunits in a calnexin-independent way. Kifunensine does not inhibit the degradation of an unglycosylated substrate (lambda Ig light chains) or of chimeric mu chains extended with the transmembrane region of the alpha T cell receptor chain, implying the existence of additional pathways for extracting proteins from the endoplasmic reticulum lumen for proteasomal degradation.
Department of Molecular Pathology and Medicine, DIBIT-San Raffaele Scientific Institute, 20132 Milan, Italy.
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D000470:Alkaloids / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003600:Cytosol / Q000201:enzymology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006023:Glycoproteins / Q000378:metabolism*; D006031:Glycosylation; D006706:Homeostasis; D006801:Humans; D007144:Immunoglobulin J-Chains / Q000378:metabolism*; D007148:Immunoglobulin mu-Chains / Q000378:metabolism*; D007700:Kinetics; D008361:Mannosidases / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism*; D009101:Multiple Myeloma; D046988:Proteasome Endopeptidase Complex; D021122:Protein Subunits; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D007144:Immunoglobulin J-Chains; D007148:Immunoglobulin mu-Chains; D009097:Multienzyme Complexes; D021122:Protein Subunits; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011993:Recombinant Fusion Proteins; C065629:kifunensine; D019284:Thapsigargin; D008361:Mannosidases; C046090:mannosyl-oligosaccharide 1,2-alpha-mannosidase; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex