title: Calpains, cleaved mini-dysferlinC72, and L-type channels underpin calcium-dependent muscle membrane repair.
abstract: Dysferlin is proposed as a key mediator of calcium-dependent muscle membrane repair, although its precise role has remained elusive. Dysferlin interacts with a new membrane repair protein, mitsugumin 53 (MG53), an E3 ubiquitin ligase that shows rapid recruitment to injury sites. Using a novel ballistics assay in primary human myotubes, we show it is not full-length dysferlin recruited to sites of membrane injury but an injury-specific calpain-cleavage product, mini-dysferlinC72. Mini-dysferlinC72-rich vesicles are rapidly recruited to injury sites and fuse with plasma membrane compartments decorated by MG53 in a process coordinated by L-type calcium channels. Collective interplay between activated calpains, dysferlin, and L-type channels explains how muscle cells sense a membrane injury and mount a specialized response in the unique local environment of a membrane injury. Mini-dysferlinC72 and MG53 form an intricate lattice that intensely labels exposed phospholipids of injury sites, then infiltrates and stabilizes the membrane lesion during repair. Our results extend functional parallels between ferlins and synaptotagmins. Whereas otoferlin exists as long and short splice isoforms, dysferlin is subject to enzymatic cleavage releasing a synaptotagmin-like fragment with a specialized protein- or phospholipid-binding role for muscle membrane repair.
authors.affiliation: Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, Sydney, NSW 2145, Australia.
authors.forename: Angela
authors.initials: A
authors.lastname: Lek
authors.forename: Frances J
authors.initials: FJ
authors.lastname: Evesson
authors.forename: Frances A
authors.initials: FA
authors.lastname: Lemckert
authors.forename: Gregory M I
authors.initials: GM
authors.lastname: Redpath
authors.forename: Ann-Katrin
authors.initials: AK
authors.lastname: Lueders
authors.forename: Lynne
authors.initials: L
authors.lastname: Turnbull
authors.forename: Cynthia B
authors.initials: CB
authors.lastname: Whitchurch
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: North
authors.forename: Sandra T
authors.initials: ST
authors.lastname: Cooper
mesh_terms: D017305:Annexin A1 / Q000378:metabolism; D002104:Cadmium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D002154:Calpain / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D000073939:Dysferlin; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000201:enzymology; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000201:enzymology* / Q000293:injuries; D049288:Muscular Dystrophies, Limb-Girdle / Q000378:metabolism* / Q000473:pathology; D010743:Phospholipids / Q000378:metabolism; D061251:Primary Cell Culture; D058088:Sarcoglycanopathies / Q000378:metabolism* / Q000473:pathology; D000070584:Tripartite Motif Proteins
chemical_list: D017305:Annexin A1; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D002352:Carrier Proteins; C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins; C118457:OTOF protein, human; D010743:Phospholipids; C558399:TRIM72 protein, human; D000070584:Tripartite Motif Proteins; D002104:Cadmium; D002154:Calpain