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© The Rockefeller University Press, 0021-9525/2003/5/521 $5.00
The Journal of Cell Biology, Volume 161, Number 3, 521-533

Proprotein convertase cleavage liberates a fibrillogenic fragment of a resident glycoprotein to initiate melanosome biogenesis

¹ Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
² Institut Curie, Centre National de la Recherche Scientifique UMR 144, 75005 Paris, France

Address correspondence to Michael S. Marks, Dept. of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, 230 John Morgan Bldg./6082, Philadelphia, PA 19104-6082. Tel.: (215) 898-3204. Fax: (215) 573-4345. E-mail: marksm{at}mail.med.upenn.edu

Lysosome-related organelles are cell type–specific intracellular compartments with distinct morphologies and functions. The molecular mechanisms governing the formation of their unique structural features are not known. Melanosomes and their precursors are lysosome-related organelles that are characterized morphologically by intralumenal fibrous striations upon which melanins are polymerized. The integral membrane protein Pmel17 is a component of the fibrils and can nucleate their formation in the absence of other pigment cell–specific proteins. Here, we show that formation of intralumenal fibrils requires cleavage of Pmel17 by a furin-like proprotein convertase (PC). As in the generation of amyloid, proper cleavage of Pmel17 liberates a lumenal domain fragment that becomes incorporated into the fibrils; longer Pmel17 fragments generated in the absence of PC activity are unable to form organized fibrils. Our results demonstrate that PC-dependent cleavage regulates melanosome biogenesis by controlling the fibrillogenic activity of a resident protein. Like the pathologic process of amyloidogenesis, the formation of other tissue-specific organelle structures may be similarly dependent on proteolytic activation of physiological fibrillogenic substrates.

Key Words: furin; endosome; proteolysis; fibril; lysosome-related organelle

^* Abbreviations used in this paper: ₁-AT, ₁-antitrypsin inhibitor; ₁-PDX, ₁-antitrypsin Portland; endoH, endoglycosidase H; IEM, immunoelectron microscopy; IFM, immunofluorescence microscopy; ILV, intralumenal vesicle; moi, multiplicity of infection; MVB, multivesicular body; PC, proprotein convertase; tTA, tetracycline-repressible transactivator; TX, Triton X-100.

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