Journal
JOURNAL OF CELL SCIENCE
Volume 130, Issue 5, Pages 841-852Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.198861
Keywords
Dysferlin; T-tubule system; Muscular dystrophy; Dysferlinopathy; Phosphatidylinositol 4, 5-bisphosphate; C2 domain protein; Limb-girdle; muscular dystrophy type 2B; Miyoshi myopathy
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Funding
- Deutsche Forschungsgemeinschaft (DFG) [KL1868/2-1, KL1868/5-1, TH 1538/1-1, SFB1002/2 TP A10]
- Hunsmann-Stiftung
- State of Lower-Saxony, Hannover, Germany [ZN2921]
- DFG International Research Training Group [GRK 1816]
- Deutsches Zentrum fur HerzKreislaufforschung (German Centre for Cardiovascular Research)
- Eva Luise and Horst Kohler Foundation
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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.
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