1. Dysferlin mediates membrane tubulation and links T-tubule biogenesis to muscular dystrophy.
- Author
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Hofhuis J, Bersch K, Büssenschütt R, Drzymalski M, Liebetanz D, Nikolaev VO, Wagner S, Maier LS, Gärtner J, Klinge L, and Thoms S
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Animals, COS Cells, Calcium metabolism, Caveolin 3 metabolism, Chlorocebus aethiops, Dynamins metabolism, Dysferlin, HeLa Cells, Humans, Membrane Proteins deficiency, Mice, Knockout, Muscle Proteins deficiency, Muscular Dystrophies pathology, Nerve Tissue Proteins metabolism, Phenotype, Phosphatidylinositol 4,5-Diphosphate metabolism, Physical Conditioning, Animal, Protein Binding, Sarcolemma ultrastructure, Tumor Suppressor Proteins metabolism, Membrane Proteins metabolism, Muscle Proteins metabolism, Muscular Dystrophies metabolism, Sarcolemma metabolism
- Abstract
The multi-C2 domain protein dysferlin localizes to the plasma membrane and the T-tubule system in skeletal muscle; however, its physiological mode of action is unknown. Mutations in the DYSF gene lead to autosomal recessive limb-girdle muscular dystrophy type 2B and Miyoshi myopathy. Here, we show that dysferlin has membrane tubulating capacity and that it shapes the T-tubule system. Dysferlin tubulates liposomes, generates a T-tubule-like membrane system in non-muscle cells, and links the recruitment of phosphatidylinositol 4,5-bisphosphate to the biogenesis of the T-tubule system. Pathogenic mutant forms interfere with all of these functions, indicating that muscular wasting and dystrophy are caused by the dysferlin mutants' inability to form a functional T-tubule membrane system., (© 2017. Published by The Company of Biologists Ltd.)
- Published
- 2017
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