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Human Molecular Genetics Advance Access published online on November 30, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi434
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received September 26, 2005
Accepted November 20, 2005

Article

Aberrant dysferlin trafficking in cells lacking caveolin or expressing dystrophy mutants of caveolin-3

Delia J. Hernández-Deviez 1, Sally Martin 1, Steven H. Laval 2, Harriet P. Lo 3, Sandra T. Cooper 3, Kathryn N. North 3, Kate Bushby 2, and Robert G. Parton 1 *

1 Institute for Molecular Bioscience, Centre for Microscopy and Microanalysis and School of Biomedical Sciences, University of Queensland, Brisbane, QLD 4072, Australia
2 LGMD Group, Institute of Human Genetics, International Centre for Life, Newcastle, NE1 3BZ, UK
3 Institute for Neuromuscular Research, Faculty of Medicine, University of Sydney, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, 2145, Sydney, Australia

* To whom correspondence should be addressed.
Robert G. Parton, E-mail: R.Parton{at}imb.uq.edu.au


  Abstract

Mutations in the dysferlin (DYSF) and caveolin-3 (CAV3) genes are associated with muscle disease. Dysferlin is mislocalized by an unknown mechanism in muscle from patients with mutations in caveolin-3 (Cav-3). To examine the link between Cav-3 mutations and dysferlin mistargeting, we studied their localization at high resolution in muscle fibers, in a model muscle cell line, and upon heterologous expression of dysferlin in muscle cell lines and in wild type or caveolin-null fibroblasts. Dysferlin shows only partial overlap with Cav-3 on the surface of isolated muscle fibers but colocalizes with Cav-3 in developing transverse (T) -tubules in muscle cell lines. Heterologously-expressed dystrophy-associated mutant Cav3R26Q accumulates in the Golgi complex of muscle cell lines or fibroblasts. Cav3R26Q and other Golgi-associated mutants of both Cav-3 (Cav3P104L) and Cav-1 (Cav1P132L) caused a dramatic redistribution of dysferlin to the Golgi complex. Heterologously-expressed epitope-tagged dysferlin associates with the plasma membrane (PM) in primary fibroblasts and muscle cells. Transport to the cell surface is impaired in the absence of Cav-1 or Cav-3 showing that caveolins are essential for dysferlin association with the PM. These results suggest a functional role for caveolins in a novel post-Golgi trafficking pathway followed by dysferlin.


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