Caveolin Muscle Repair

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Caveolin Regulates Endocytosis of the Muscle Repair Protein, Dysferlin * S Received for publication, October 24, 2007, and in revised form, November 26, 2007 Published, JBC Papers in Press, December 20, 2007, DOI 10.1074/jbc.M708776200 Delia J. Herna ´ndez-Deviez , Mark T. Howes , Steven H. Laval § , Kate Bushby § , John F. Hancock , and Robert G. Parton ‡¶1 From the Institute for Molecular Bioscience, Centre for Microscopy and Microanalysis, University of Queensland, Brisbane, Queensland 4072, Australia and the § Institute of Human Genetics, International, Centre for Life, Newcastle NE1 3BZ, United Kingdom Dysferlin and Caveolin-3 are plasma membrane proteins associated with muscular dystrophy. Patients with mutations in the CAV3 gene show dysferlin mislocalization in muscle cells. By utilizing caveolin-null cells, expression of caveolin mutants, and different mutants of dysferlin, we have dis- sected the site of action of caveolin with respect to dysferlin trafficking pathways. We now show that Caveolin-1 or -3 can facilitate exit of a dysferlin mutant that accumulates in the Golgi complex of Cav1 ± / ± cells. In contrast, wild type dysfer- lin reaches the plasma membrane but is rapidly endocytosed in Cav1 ± / ± cells. We demonstrate that the primary effect of caveolin is to cause surface retention of dysferlin. Caveolin-1 or Caveolin-3, but not specific caveolin mutants, inhibit endocytosis of dysferlin through a clathrin-independent pathway colocalizing with internalized glycosylphosphatidy- linositol-anchored proteins. Our results provide new insights into the role of this endocytic pathway in surface remodeling of specific surface components. In addition, they highlight a novel mechanism of action of caveolins relevant to the pathogenic mechanisms underlying caveolin-associated disease. Dysferlin and Caveolin-3 (muscle-specific caveolin, Cav3) are sarcolemmal proteins whose role in muscle has gained clin- ical attention because mutations in their genes are associated with a number of muscle pathologies. Patients with mutations in the dysferlin ( DYSF ) gene develop disorders such as limb girdle muscular dystrophy type 2B, miyoshi myopathy, and dis- tal myopathy (1–5). Whereas disruption in the Caveolin-3 ( CAV3 ) gene has been linked to limb girdle muscular dystrophy 1C, Rippling muscle diseases, hyperCKemia, and distal myopa- thy among other myopathies (6–15). Dysferlin and Cav3 have been co-purified from muscle cells (16, 17) and shown to local- ize to adjacent membrane domains at the surface in mature muscle fibers (18). Moreover, dysferlin is depleted from the plasma membrane (PM) 2 when Cav3 is mutated (8, 9, 14, 17, 19). We have recently demonstrated a role for caveolin in dys- ferlin localization at the PM (18). However, the interplay of dysferlin and caveolin membrane trafficking dynamics remains to be examined.
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