SLIMMER (FHL1B/KyoT3) interacts with the proapoptotic protein Siva-1 (CD27BP) and delays skeletal myoblast apoptosis.
The fhl1 gene encoding four-and-a-half LIM protein-1 (FHL1) and its spliced isoform, SLIMMER, is mutated in reducing body myopathy, X-linked myopathy with postural muscle atrophy, scapuloperoneal myopathy, and rigid spine syndrome. In this study we have identified a novel function for SLIMMER in delaying skeletal muscle apoptosis via an interaction with the proapoptotic protein Siva-1. Siva-1 was identified as a SLIMMER-specific-interacting protein using yeast two-hybrid screening, direct-binding studies, and glutathione S-transferase pulldown analysis of murine skeletal muscle lysates. In C2C12 skeletal myoblasts, SLIMMER and Siva co-localized in the nucleus; however, both proteins exhibited redistribution to the cytoplasm following the differentiation of mononucleated myoblasts to multinucleated myotubes. In sections of mature skeletal muscle from wild type mice, SLIMMER and Siva-1 co-localized at the Z-line. SLIMMER and Siva-1 were also enriched in Pax-7-positive satellite cells, muscle stem cells that facilitate repair and regeneration. Significantly, SLIMMER delayed Siva-1-dependent apoptosis in C2C12 myoblasts. In skeletal muscle sections from the mdx mouse model of Duchenne muscular dystrophy, SLIMMER and Siva-1 co-localized in the nucleus of apoptotic myofibers. Therefore, SLIMMER may protect skeletal muscle from apoptosis.
Cottle
Denny L
DL
Department of Biochemistry and Molecular Biology, Monash University, Clayton, 3800 Victoria, Australia.
McGrath
Meagan J
MJ
Wilding
Brendan R
BR
Cowling
Belinda S
BS
Kane
Jordan M
JM
D'Arcy
Colleen E
CE
Holdsworth
Melissa
M
Hatzinisiriou
Irene
I
Prescott
Mark
M
Brown
Susan
S
Mitchell
Christina A
CA
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001665:Binding Sites; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D005260:Female; D005434:Flow Cytometry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D060588:LIM Domain Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018613:Microscopy, Confocal; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D020798:Two-Hybrid System Techniques
D051017:Apoptosis Regulatory Proteins; C486306:Fhl1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D009124:Muscle Proteins; D020033:Protein Isoforms; C484569:Siva protein, mouse