Aberrant dysferlin trafficking in cells lacking caveolin or expressing dystrophy mutants of caveolin-3.
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.
Hernández-Deviez
Delia J
DJ
Institute for Molecular Bioscience, Centre for Microscopy and Microanalysis and School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
Martin
Sally
S
Laval
Steven H
SH
Lo
Harriet P
HP
Cooper
Sandra T
ST
North
Kathryn N
KN
Bushby
Kate
K
Parton
Robert G
RG
D000818:Animals; D051244:Caveolin 3 / Q000172:deficiency* / Q000235:genetics*; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D000073939:Dysferlin; D005260:Female; D006056:Golgi Apparatus / Q000378:metabolism; D015151:Immunoblotting; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008856:Microscopy, Fluorescence; D016253:Microscopy, Immunoelectron; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D021381:Protein Transport / Q000502:physiology
C495548:Cav3 protein, mouse; D051244:Caveolin 3; C497505:Dysf protein, mouse; D000073939:Dysferlin; D008565:Membrane Proteins