NF-κB-dependent expression of the antiapoptotic factor c-FLIP is regulated by calpain 3, the protein involved in limb-girdle muscular dystrophy type 2A

被引:43
作者
Benayoun, Beatrice [1 ]
Baghdiguian, Stephen [2 ]
Lajmanovich, Alicia [3 ]
Bartoli, Marc [1 ]
Daniele, Nathalie [1 ]
Gicquel, Evelyne [1 ]
Bourg, Nathalie [1 ]
Raynaud, Fabrice [4 ]
Pasquier, Marie-Anne [3 ]
Suel, Laurence [1 ]
Lochmuller, Hanns [5 ,6 ]
Lefranc, Gerard [2 ,7 ]
Richard, Isabelle [1 ]
机构
[1] CNRS, Genethon FRE 3018, F-91000 Evry, France
[2] Univ Montpellier 2, CNRS, UMR 5554, Montpellier, France
[3] INSERM, Albert Bonniot Inst, EMI 353, Res Grp Lymphoma, La Tronche, France
[4] IGF, UMR 5203, Dept Neurosci, Montpellier, France
[5] Univ Munich, Friedrich Baur Inst, Munich, Germany
[6] Univ Munich, Dept Neurol, D-8000 Munich, Germany
[7] CNRS, UPR 1142, Inst Genet Humaine, Lab Immunol Mol, Montpellier, France
基金
英国医学研究理事会;
关键词
muscle; apoptosis; FLICE; inhibitary protein; lgmd2A;
D O I
10.1096/fj.07-8701com
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-kappa B/I kappa B alpha survival pathway. In this study, the consequences of altered NF-kappa B/I kappa B alpha pathway were investigated using biological materials from LGMD2A patients. We first show that die antiapoptotic factor cellular-FUCE inhibitory protein (c-FLIP), which is dependent on the NF-kappa B pathway in normal muscle cells, is down-regulated in LGMD2A biopsies. In muscle cells isolated from LGMD2A patients, NF-kappa B 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-kappa B target genes. I kappa B alpha is expressed following NF-kappa B 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-kappa B-dependent survival genes to prevent apoptosis in skeletal muscle. Deregulations in the NF-kappa B pathway could be part of the mechanism responsible for the muscle wasting resulting from CAPN3 deficiency.
引用
收藏
页码:1521 / 1529
页数:9
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