NF-kappaB-dependent expression of the antiapoptotic factor c-FLIP is regulated by calpain 3, the protein involved in limb-girdle muscular dystrophy type 2A.
Limb-girdle muscular dystrophy type 2A (LGMD2A) is a recessive genetic disorder caused by mutations in the cysteine protease calpain 3 (CAPN3) that leads to selective muscle wasting. We previously showed that CAPN3 deficiency is associated with a profound perturbation of the NF-kappaB/IkappaB alpha survival pathway. In this study, the consequences of altered NF-kappaB/IkappaB alpha pathway were investigated using biological materials from LGMD2A patients. We first show that the antiapoptotic factor cellular-FLICE inhibitory protein (c-FLIP), which is dependent on the NF-kappaB pathway in normal muscle cells, is down-regulated in LGMD2A biopsies. In muscle cells isolated from LGMD2A patients, NF-kappaB is readily activated on cytokine induction as shown by an increase in its DNA binding activity. However, we observed discrepant transcriptional responses depending on the NF-kappaB target genes. IkappaB alpha is expressed following NF-kappaB activation independent of the CAPN3 status, whereas expression of c-FLIP is obtained only when CAPN3 is present. These data lead us to postulate that CAPN3 intervenes in the regulation of the expression of NF-kappaB-dependent survival genes to prevent apoptosis in skeletal muscle. Deregulations in the NF-kappaB pathway could be part of the mechanism responsible for the muscle wasting resulting from CAPN3 deficiency.
Benayoun
Béatrice
B
Généthon CNRS FRE3018, 1, 91000 Evry, France.
Baghdiguian
Stephen
S
Lajmanovich
Alicia
A
Bartoli
Marc
M
Daniele
Nathalie
N
Gicquel
Evelyne
E
Bourg
Nathalie
N
Raynaud
Fabrice
F
Pasquier
Marie-Anne
MA
Suel
Laurence
L
Lochmuller
Hanns
H
Lefranc
Gérard
G
Richard
Isabelle
I
D017209:Apoptosis / Q000502:physiology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000096:biosynthesis*; D002154:Calpain / Q000172:deficiency / Q000502:physiology*; D002478:Cells, Cultured; D015536:Down-Regulation; D006801:Humans; D020672:I-kappa B Proteins / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000502:physiology; D008954:Models, Biological; D009124:Muscle Proteins / Q000172:deficiency / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism; D049288:Muscular Dystrophies, Limb-Girdle / Q000503:physiopathology*; D016328:NF-kappa B / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis; D051020:bcl-X Protein / Q000096:biosynthesis
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D009124:Muscle Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C105884:CAPN3 protein, human; D002154:Calpain