Cut protein to boost fibers
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《细胞学杂志》
In a new analysis of melanosome biogenesis, Berson et al. (page 521) demonstrate that the proteolytic cleavage of a glycoprotein drives the formation of the characteristic fibrous striations seen in these organelles. The work uncovers a general mechanism that may regulate the development of lysosome-related organelles in a variety of cell types, and also shows a striking parallel between the experimentally tractable melanocyte system and the complex pathogenesis of amyloid diseases.Melanosomes, specialized organelles that store melanin pigments, develop intralumenal fibrils superficially similar to those seen in amyloid diseases, but little is known about how these fibrils form. Previous work identified an apparent paradox, suggesting that the melanosome fibrils do not contain membrane, but do contain the integral membrane glycoprotein Pmel17.
The new work resolves this issue, showing that Pmel17 must be cleaved by proprotein convertases to initiate fibril formation. A cleavage product is eventually released into the lumen of the melanosome and incorporated into fibrils. Since many cell types develop specialized lysosome-related organelles, proprotein convertases or other proteases may be general initiators of similar morphogenetic processes for a wide range of organelles.
Besides illuminating a previously obscure aspect of organelle biogenesis, the work suggests a strong similarity between normal melanosome fibril formation and the pathogenic fibril formation that occurs in amyloid diseases. Some pathogenic amyloid proteins are specifically cleaved by proprotein convertases, and proteolytic processing is also a general feature of Alzheimer's disease and prion diseases. Berson et al. propose that proteolytic maturation is a normal step in lysosome-related organelle biogenesis, and pathogenic variations in the process may drive inherited organelle defects as well as amyloid diseases. The authors are now trying to reproduce melanosome fibril formation in vitro, and hope to use the system as a model for understanding both normal and pathogenic fibril formation.(Cleavage site deficient Pme17 localizes )
The new work resolves this issue, showing that Pmel17 must be cleaved by proprotein convertases to initiate fibril formation. A cleavage product is eventually released into the lumen of the melanosome and incorporated into fibrils. Since many cell types develop specialized lysosome-related organelles, proprotein convertases or other proteases may be general initiators of similar morphogenetic processes for a wide range of organelles.
Besides illuminating a previously obscure aspect of organelle biogenesis, the work suggests a strong similarity between normal melanosome fibril formation and the pathogenic fibril formation that occurs in amyloid diseases. Some pathogenic amyloid proteins are specifically cleaved by proprotein convertases, and proteolytic processing is also a general feature of Alzheimer's disease and prion diseases. Berson et al. propose that proteolytic maturation is a normal step in lysosome-related organelle biogenesis, and pathogenic variations in the process may drive inherited organelle defects as well as amyloid diseases. The authors are now trying to reproduce melanosome fibril formation in vitro, and hope to use the system as a model for understanding both normal and pathogenic fibril formation.(Cleavage site deficient Pme17 localizes )