Proteasome inhibitors block a late step in lysosomal transport of selected membrane but not soluble proteins.
The ubiquitin-proteasome pathway acts as a regulator of the endocytosis of selected membrane proteins. Recent evidence suggests that it may also function in the intracellular trafficking of membrane proteins. In this study, several models were used to address the role of the ubiquitin-proteasome pathway in sorting of internalized proteins to the lysosome. We found that lysosomal degradation of ligands, which remain bound to their receptors within the endocytic pathway, is blocked in the presence of specific proteasome inhibitors. In contrast, a ligand that dissociates from its receptor upon endosome acidification is degraded under the same conditions. Quantitative electron microscopy showed that neither the uptake nor the overall distribution of the endocytic marker bovine serum albumin-gold is substantially altered in the presence of a proteasome inhibitor. The data suggest that the ubiquitin-proteasome pathway is involved in an endosomal sorting step of selected membrane proteins to lysosomes, thereby providing a mechanism for regulated degradation.
van Kerkhof
P
P
Department of Cell Biology, University Medical Center Utrecht, 3584CX Utrecht, The Netherlands.
Alves dos Santos
C M
CM
Sachse
M
M
Klumperman
J
J
Bu
G
G
Strous
G J
GJ
D000818:Animals; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004705:Endocytosis / Q000502:physiology; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D008024:Ligands; D008247:Lysosomes / Q000378:metabolism* / Q000648:ultrastructure; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D021381:Protein Transport / Q000502:physiology*; D020917:Receptor, trkA / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000235:genetics / Q000378:metabolism*; D014168:Transferrin / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D007783:Lactones; D007976:Leupeptins; D008024:Ligands; D009097:Multienzyme Complexes; D011986:Receptors, Somatotropin; D014168:Transferrin; C098869:clasto-lactacystin beta-lactone; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde