Proprotein convertase cleavage liberates a fibrillogenic fragment of a resident glycoprotein to initiate melanosome biogenesis.
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.
Dept. of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6082, USA.
Joanne F
JF
Berson
Alexander C
AC
Theos
Dawn C
DC
Harper
Danielle
D
Tenza
Graça
G
Raposo
Michael S
MS
Marks
D002451:Cell Compartmentation / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D003902:Detergents / Q000494:pharmacology; D011992:Endosomes / Q000378:metabolism / Q000648:ultrastructure; D005057:Eukaryotic Cells / Q000201:enzymology* / Q000648:ultrastructure; D006023:Glycoproteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008543:Melanins / Q000378:metabolism; D020460:Melanosomes / Q000201:enzymology* / Q000648:ultrastructure; D008562:Membrane Glycoproteins; D020894:Microfibrils / Q000201:enzymology* / Q000648:ultrastructure; D008854:Microscopy, Electron; D017830:Octoxynol / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000378:metabolism; D043484:Proprotein Convertases; D017434:Protein Structure, Tertiary / Q000502:physiology; D011506:Proteins / Q000378:metabolism*; D012995:Solubility / Q000187:drug effects; D013381:Subtilisins / Q000378:metabolism*; D058951:gp100 Melanoma Antigen
D003902:Detergents; D006023:Glycoproteins; D008543:Melanins; D008562:Membrane Glycoproteins; C548637:PMEL protein, human; D011506:Proteins; D058951:gp100 Melanoma Antigen; D017830:Octoxynol; D010447:Peptide Hydrolases; D043484:Proprotein Convertases; D013381:Subtilisins