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

Béatrice Benayoun^*, Stephen Baghdiguian, Alicia Lajmanovich, Marc Bartoli^*, Nathalie Daniele^*, Evelyne Gicquel^*, Nathalie Bourg^*, Fabrice Raynaud, Marie-Anne Pasquier, Laurence Suel^*, Hanns Lochmuller^||,1, Gérard Lefranc^¶ and Isabelle Richard^*,2

^* Généthon CNRS FRE 3018, Evry, France;

Université Montpellier 2, CNRS UMR 5554, Montpellier, France;

The Research Group on Lymphoma, INSERM, EMI 353, Albert Bonniot Institute, La Tronche, France;

IGF, UMR 5203, Département de Neuroscience, Montpellier, France;

^|| Friedrich-Baur-Institute and Department of Neurology, Ludwig-Maximilians-University, Munich, Germany; and

^¶ Laboratoire d’Immunologie Moléculaire, Institut de Génétique Humaine, CNRS UPR 1142, and Université Montpellier 2, Montpellier, France

²Correspondence: Généthon CNRS FRE3018, 1, rue de l’internationale, 91000 Evry, France. Email: richard{at}genethon.fr

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-B/IB survival pathway. In this study, the consequences of altered NF-B/IB 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-B pathway in normal muscle cells, is down-regulated in LGMD2A biopsies. In muscle cells isolated from LGMD2A patients, NF-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-B target genes. IB is expressed following NF-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-B-dependent survival genes to prevent apoptosis in skeletal muscle. Deregulations in the NF-B pathway could be part of the mechanism responsible for the muscle wasting resulting from CAPN3 deficiency.—Benayoun, B., Baghdiguian, S., Lajmanovich, A., Bartoli, M., Daniele, N., Gicquel, E., Bourg, N., Raynaud, F., Pasquier, M.-A., Suel, L., Lochmuller, H., Lefranc, G., Richard, I. NF-B-dependent expression of the antiapoptotic factor c-FLIP is regulated by calpain 3, the protein involved in limb-girdle muscular dystrophy type 2A.

Key Words: muscle • apoptosis • FLICE inhibitory protein • lgmd2A

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