title: Mislocalization of melanosomal proteins in melanocytes from mice with oculocutaneous albinism type 2.
abstract: More than 10% of admissions worldwide to institutions for the visually impaired are due to some form of albinism. The most common form, oculocutaneous albinism type 2, results from mutations at the p locus. The function of the p gene is yet to be determined. It has been shown that melanocytes from p -null mice exhibit an abnormal melanosomal ultrastructure in addition to alterations in activity and localization of tyrosinase, a critical melanogenic enzyme. In light of these observations, we examined tyrosinase trafficking in p -null vs wildtype mouse melanocytes in order to explore p function. Electron microscopy of wildtype melan-a and p -null melan-p1 cells demonstrated accumulation of tyrosinase in 50 nm vesicles throughout the cell in the absence of p, an observation corroborated by an increase in tyrosinase activity in vesicle-enriched fractions from melan-p1 compared to melan-a cells. Misrouting in the absence of p was not limited to tyrosinase; a second melanosomal protein, tyrosinase-related protein 1, also trafficked incorrectly. In melan-p1, mislocalization led to secretion of tyrosinase into the medium. Adding tyrosine to the medium was found to partially correct tyrosinase trafficking and to reduce secretion; the cysteine protease inhibitor E64 also reduced secretion. We propose that p is required by melanocytes for transport of melanosomal proteins. In its absence, tyrosinase accumulates in vesicles and, in cultured melanocytes, is proteolysed and secreted.
authors.affiliation: The Ronald O. Perelman Department of Dermatology and The Department of Cell Biology, New York University, School of Medicine, New York, NY 10016, USA.
authors.forename: P
authors.initials: P
authors.lastname: Manga
authors.forename: R E
authors.initials: RE
authors.lastname: Boissy
authors.forename: S
authors.initials: S
authors.lastname: Pifko-Hirst
authors.forename: B K
authors.initials: BK
authors.lastname: Zhou
authors.forename: S J
authors.initials: SJ
authors.lastname: Orlow
mesh_terms: D016115:Albinism, Oculocutaneous / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D006056:Golgi Apparatus / Q000378:metabolism; D006868:Hydrolysis; D008544:Melanocytes / Q000378:metabolism* / Q000648:ultrastructure; D020460:Melanosomes / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D014442:Monophenol Monooxygenase / Q000378:metabolism
chemical_list: D014442:Monophenol Monooxygenase