Ubiquitylation of a melanosomal protein by HECT-E3 ligases serves as sorting signal for lysosomal degradation

The production of pigment by melanocytic cells of the skin involves a series of enzymatic reactions that take place in specialized organelles called melanosomes. Melan-A/MART-1 is a melanocytic transmembrane protein with no enzymatic activity that accumulates in vesicles at the trans side of the Gol...

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Bibliographic Details
Published in:Molecular biology of the cell 2005-04, Vol.16 (4), p.1777-1787
Main Authors: Lévy, Frédéric, Muehlethaler, Katja, Salvi, Suzanne, Peitrequin, Anne-Lise, Lindholm, Cecilia K, Cerottini, Jean-Charles, Rimoldi, Donata
Format: Article
Language:English
Subjects:
Antigens, Neoplasm
Cell Line
Endosomal Sorting Complexes Required for Transport
Humans
Lysosomes - metabolism
MART-1 Antigen
Melanosomes - chemistry
Melanosomes - metabolism
Nedd4 Ubiquitin Protein Ligases
Neoplasm Proteins - genetics
Neoplasm Proteins - metabolism
Proteasome Endopeptidase Complex - genetics
Proteasome Endopeptidase Complex - metabolism
Protein Binding
Repressor Proteins - genetics
Repressor Proteins - metabolism
Ubiquitin - metabolism
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
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Summary:The production of pigment by melanocytic cells of the skin involves a series of enzymatic reactions that take place in specialized organelles called melanosomes. Melan-A/MART-1 is a melanocytic transmembrane protein with no enzymatic activity that accumulates in vesicles at the trans side of the Golgi and in melanosomes. We show here that, in melanoma cells, Melan-A associates with two homologous to E6-AP C-terminus (HECT)-E3 ubiquitin ligases, NEDD4 and Itch, and is ubiquitylated. Both NEDD4 and Itch participate in the degradation of Melan-A. A mutant Melan-A lacking ubiquitin-acceptor residues displays increased half-life and, in pigmented cells, accumulates in melanosomes. These results suggest that ubiquitylation regulates the lysosomal sorting and degradation of Melan-A/MART-1 from melanosomes in melanocytic cells.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.E04-09-0803