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Mol Biol Cell. 2014 Oct 1;25(19):3037-48. doi: 10.1091/mbc.E14-04-0947. Epub 2014 Aug 20.

Calpain cleavage within dysferlin exon 40a releases a synaptotagmin-like module for membrane repair.

Author information

1
Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, Sydney, NSW 2145, Australia Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, Australia.
2
Department of Pathology and Molecular Medicine, Queen's University, Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, Kingston, ON K7L 3N6, Canada.
3
Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC, Australia, and Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, VIC 3010, Australia.
4
Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, Sydney, NSW 2145, Australia Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, Australia sandra.cooper@sydney.edu.au.

Abstract

Dysferlin and calpain are important mediators of the emergency response to repair plasma membrane injury. Our previous research revealed that membrane injury induces cleavage of dysferlin to release a synaptotagmin-like C-terminal module we termed mini-dysferlinC72. Here we show that injury-activated cleavage of dysferlin is mediated by the ubiquitous calpains via a cleavage motif encoded by alternately spliced exon 40a. An exon 40a-specific antibody recognizing cleaved mini-dysferlinC72 intensely labels the circumference of injury sites, supporting a key role for dysferlinExon40a isoforms in membrane repair and consistent with our evidence suggesting that the calpain-cleaved C-terminal module is the form specifically recruited to injury sites. Calpain cleavage of dysferlin is a ubiquitous response to membrane injury in multiple cell lineages and occurs independently of the membrane repair protein MG53. Our study links calpain and dysferlin in the calcium-activated vesicle fusion of membrane repair, placing calpains as upstream mediators of a membrane repair cascade that elicits cleaved dysferlin as an effector. Of importance, we reveal that myoferlin and otoferlin are also cleaved enzymatically to release similar C-terminal modules, bearing two C2 domains and a transmembrane domain. Evolutionary preservation of this feature highlights its functional importance and suggests that this highly conserved C-terminal region of ferlins represents a functionally specialized vesicle fusion module.

PMID:
25143396
PMCID:
PMC4230592
DOI:
10.1091/mbc.E14-04-0947
[Indexed for MEDLINE]
Free PMC Article

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