title: Aminopeptidase-resistant peptides are targeted to lysosomes and subsequently degraded.
abstract: Most cytoplasmic and nuclear proteins are degraded via the ubiquitin-proteasome system into peptides, which are subsequently hydrolyzed by downstream aminopeptidases. Inefficient degradation can lead to accumulation of protein fragments, and subsequent aggregation and toxicity. Whereas the role of the proteasome and the effect of its impairment on aggregation have been intensively studied, little is known about how cells deal with peptides that show resistance to degradation by aminopeptidases. Here, we introduced peptidase-resistant peptides into living cells and show that these peptides rapidly and irreversibly accumulate into puncta in the perinuclear region of the cell. Accumulation appears to be independent of peptide sequence but is less efficient for longer peptides. The puncta colocalize with autophagosomal and lysosomal markers, suggesting that these peptides end up within lysosomes via macroautophagy. Surprisingly, the peptides still accumulate within lysosomes when macroautophagy is impaired, suggesting a trafficking route independent of macroautophagy. Upon lysosomal uptake, peptides are degraded, suggesting that cells can clear peptidase-resistant proteasomal products by an alternative pathway, which targets them to lysosomes.
authors: Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, the Netherlands.
authors: Judith M
authors: JM
authors: Gillis
authors: Willemien
authors: W
authors: Benckhuijsen
authors: Henk
authors: H
authors: van Veen
authors: Alicia Sanz
authors: AS
authors: Sanz
authors: Jan W
authors: JW
authors: Drijfhout
authors: Eric A
authors: EA
authors: Reits
mesh_terms: D000626:Aminopeptidases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D020033:Protein Isoforms; D059748:Proteolysis
chemical_list: D018840:HSP70 Heat-Shock Proteins; D010455:Peptides; D020033:Protein Isoforms; D000626:Aminopeptidases; D046988:Proteasome Endopeptidase Complex