Glycoprotein quality control in the endoplasmic reticulum. Mannose trimming by endoplasmic reticulum mannosidase I times the proteasomal degradation of unassembled immunoglobulin subunits

• Published in: The Journal of biological chemistry 2001-04, Vol.276 (16), p.12885-12892
• Main Authors: Fagioli, C, Sitia, R
• Format: Article
• Language: English
• Subjects: Alkaloids - pharmacology; Cysteine Endopeptidases - metabolism; Cytosol - enzymology; Endoplasmic Reticulum - metabolism; Enzyme Inhibitors - pharmacology; Glycoproteins - metabolism; Glycosylation; Homeostasis; Humans; Immunoglobulin J-Chains - metabolism; Immunoglobulin mu-Chains - metabolism; kifunensine; Kinetics; mannosidase I; mannosidase II; Mannosidases - metabolism; Multienzyme Complexes - metabolism; Multiple Myeloma; Proteasome Endopeptidase Complex; Protein Subunits; Receptors, Antigen, T-Cell, alpha-beta - metabolism; Recombinant Fusion Proteins - metabolism; swainsonine; Thapsigargin - pharmacology; Tumor Cells, Cultured
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M009603200

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.