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 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.
Lévy
Frédéric
F
Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland. donata.rimoldi@isrec.unil.ch
Muehlethaler
Katja
K
Salvi
Suzanne
S
Peitrequin
Anne-Lise
AL
Lindholm
Cecilia K
CK
Cerottini
Jean-Charles
JC
Rimoldi
Donata
D
D000951:Antigens, Neoplasm; D002460:Cell Line; D056827:Endosomal Sorting Complexes Required for Transport; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D058965:MART-1 Antigen; D020460:Melanosomes / Q000737:chemistry / Q000378:metabolism*; D000075702:Nedd4 Ubiquitin Protein Ligases; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D000951:Antigens, Neoplasm; D056827:Endosomal Sorting Complexes Required for Transport; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D025801:Ubiquitin; C432966:ITCH protein, human; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex