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Papers In Press, published online ahead of print March 3, 2006
Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, PA 15261
Corresponding Author: weisz{at}pitt.edu
Mucolipin-1 (ML1) is a member of the TRP ion channel superfamily that is thought to function in the biogenesis of lysosomes. Mutations in ML1 result in mucolipidosis type IV, a lysosomal storage disease characterized by the intracellular accumulation of enlarged vacuolar structures containing phospholipids, sphingolipids, and mucopolysaccharides. Little is known about how ML1 trafficking or activity are regulated. Here we have examined the processing and trafficking of ML1 in a variety of cell types. We find that a significant fraction of ML1 undergoes cell-type independent cleavage within the first extracellular loop of the protein during a late step in its biosynthetic delivery. To determine the trafficking route of ML1, we systematically examined the effect of ablating adaptor protein complexes on the localization of this protein. Whereas ML1 trafficking was not apparently affected in fibroblasts from mocha mice that lack functional AP-3, siRNA-mediated knockdown revealed a requirement for AP-1 in Golgi export of ML1. Knockdown of functional AP-2 had no effect on ML1 localization. Interestingly, cleavage of ML1 was not compromised in AP-1 deficient cells, suggesting that proteolysis occurs in a prelysosomal compartment, possibly the trans-Golgi network. Our results suggest that posttranslational processing of ML1 is more complex than previously described, and that this protein is delivered to lysosomes primarily via an AP-1 dependent route that does not involve passage via the cell surface.
J. Biol. Chem, 10.1074/jbc.M511104200
Submitted on October 12, 2005
Accepted on March 3, 2006
Posttranslational cleavage and adaptor protein complex-dependent trafficking of mucolipin-1
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