Abstract |
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.
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Authors | C Fagioli, R Sitia |
Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 276
Issue 16
Pg. 12885-92
(Apr 20 2001)
ISSN: 0021-9258 [Print] United States |
PMID | 11278527
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Alkaloids
- Enzyme Inhibitors
- Glycoproteins
- Immunoglobulin J-Chains
- Immunoglobulin mu-Chains
- Multienzyme Complexes
- Protein Subunits
- Receptors, Antigen, T-Cell, alpha-beta
- Recombinant Fusion Proteins
- kifunensine
- Thapsigargin
- Mannosidases
- mannosyl-oligosaccharide 1,2-alpha-mannosidase
- Cysteine Endopeptidases
- Proteasome Endopeptidase Complex
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Topics |
- 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)
- Kinetics
- Mannosidases
(metabolism)
- Multienzyme Complexes
(metabolism)
- Multiple Myeloma
- Proteasome Endopeptidase Complex
- Protein Subunits
- Receptors, Antigen, T-Cell, alpha-beta
(metabolism)
- Recombinant Fusion Proteins
(metabolism)
- Thapsigargin
(pharmacology)
- Tumor Cells, Cultured
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