Calpain cleavage within dysferlin exon 40a releases a synaptotagmin-like module for membrane repair.
Bottom Line: 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.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.
Affiliation: 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.Show MeSH
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Mentions: Although skeletal muscle is believed to be particularly prone to membrane injury due to its contractile functions under load, membrane injury is also a feature of ischemic injury to heart and brain and shear stress injury of blood vessel endothelia. Because dysferlin is ubiquitously expressed and readily detected in endothelia and brain, we studied whether the calcium-activated calpain cleavage of dysferlin represents a ubiquitous response to acute membrane injury or is a specific adaptation of skeletal muscle. In primary cultures of human myotubes, human umbilical vein endothelial cells (HUVECs), mouse astrocytes, and microglia, as well as secondary human oligodendrocytes (MO3.13), each displayed calcium-dependent, calpeptin-sensitive formation of mini-dysferlinC72 after scrape damage (Figure 4A). Primary mouse astrocytes and HUVECs do not express detectable levels of MG53 but are still capable of forming mini-dysferlinC72, indicating that MG53 is not required for calpain cleavage of dysferlin (Figure 4B).
Affiliation: 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.