Removal and degradation of the free MHC class II beta chain in the endoplasmic reticulum requires proteasomes and is accelerated by BFA.
We have studied the degradation of the free major histocompatibility complex (MHC) class II beta subunit in the ER. Domain swapping experiments demonstrate that both the intra- and extracellular domain determine the rate of degradation. Recently, it has been shown that some ER-retained proteins are exported from the ER by the translocon followed by deglycosylation and degradation in the cytosol by proteasomes. Degradation of the beta chain follows a different route. The proteasome is involved but inhibition of the proteasome by lactacystin does not result in deglycosylation and export to the cytosol. Instead, the beta chain is retained in the ER implying that extraction of the beta chain from the ER membrane requires proteasome activity. Surprisingly, brefeldin A accelerates the degradation of the beta chain by the proteasome. This suggests that various processes outside the ER are involved in ER-degradation. The ER is the site from where misfolded class II beta chains enter a proteasome-dependent degradation pathway.
Divisions of Tumor Biology and Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, The Netherlands.
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Dusseljee
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Wubbolts
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D
Verwoerd
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A
Tulp
H
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Janssen
J
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Calafat
J
J
Neefjes
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D020126:Brefeldin A; D002458:Cell Fractionation; D002460:Cell Line; D003517:Cyclopentanes / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D015796:HLA-B27 Antigen / Q000235:genetics / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007668:Kidney; D018942:Macrolides; D009097:Multienzyme Complexes / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins
D000900:Anti-Bacterial Agents; D003517:Cyclopentanes; D015853:Cysteine Proteinase Inhibitors; D015796:HLA-B27 Antigen; D000949:Histocompatibility Antigens Class II; D018942:Macrolides; D009097:Multienzyme Complexes; D011500:Protein Synthesis Inhibitors; D011993:Recombinant Fusion Proteins; C067713:lactacystin; D020126:Brefeldin A; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine