The proteasome regulates receptor-mediated endocytosis of interleukin-2.
Recent studies have increasingly implicated the proteasome in the regulation of cell surface receptors. In the present study, we investigated the role of the proteasome for ligand-dependent endocytosis and degradation of the interleukin-2 (IL-2)-interleukin-2 receptor (IL-2R) complex. Proteasome inhibitors impaired internalization of IL-2.IL-2R and prevented the lysosomal degradation of this cytokine. Based on time-course studies, proteasome activity is primarily required after initial endocytosis of the IL-2.IL-2R. Proteasome function was also necessary for the lysosomal degradation of IL-2 internalized by IL-2R that were comprised of cytoplasmic tailless beta- or gamma c-subunits, suggesting that the target protein for the proteasome is independent of either the cytoplasmic tail of the IL-2R beta- or gamma c-subunits and their associated signaling components. Therefore, a functional proteasome is required for optimal endocytosis of the IL-2R/ligand complex and is essential for the subsequent lysosomal degradation of IL-2, possibly by regulating trafficking to the lysosome.
Yu
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Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida 33136, USA.
Malek
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D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D007376:Interleukin-2 / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D046911:Macromolecular Substances; D051379:Mice; D008810:Mice, Inbred C57BL; D008894:Milk Proteins; D009097:Multienzyme Complexes / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D021122:Protein Subunits; D015375:Receptors, Interleukin-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D007976:Leupeptins; D046911:Macromolecular Substances; D008894:Milk Proteins; D009097:Multienzyme Complexes; D009842:Oligopeptides; D021122:Protein Subunits; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; C090535:benzyloxycarbonyl-isoleucyl-glutamyl(O-tert-butyl)-alanyl-leucinal; C067713:lactacystin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine