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Vol. 16, Issue 4, 1777-1787, April 2005

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Ubiquitylation of a Melanosomal Protein by HECT-E3 Ligases Serves as Sorting Signal for Lysosomal Degradation

Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, CH-1066 Epalinges, Switzerland

Submitted September 14, 2004; Accepted January 31, 2005
Monitoring Editor: Juan S. Bonifacino

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.

Abbreviations used: HECT, homologous to E6-AP C-terminus; MVB, multivesicular body; Ub, ubiquitin.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Frédéric Lévy (frederic.levy{at}isrec.unil.ch) or Donata Rimoldi (donata.rimoldi{at}isrec.unil.ch).

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