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

Lookup NU author(s): Dr Steven Laval, Emerita Professor Katherine Bushby

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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 co-localizes 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 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. © The Author 2005. Published by Oxford University Press. All rights reserved.


Publication metadata

Author(s): Hernandez-Deviez DJ, Martin S, Laval SH, Lo HP, Cooper ST, North KN, Bushby K, Parton RG

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2006

Volume: 15

Issue: 1

Pages: 129-142

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/hmg/ddi434

DOI: 10.1093/hmg/ddi434

PubMed id: 16319126


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