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

DJ Hernandez-Deviez, S Martin… - Human molecular …, 2006 - academic.oup.com
DJ Hernandez-Deviez, S Martin, SH Laval, HP Lo, ST Cooper, KN North, K Bushby…
Human molecular genetics, 2006academic.oup.com
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 …
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.
Oxford University Press