Article
- The EMBO Journal (2008) 27, 1266 - 1276
- doi:10.1038/emboj.2008.52
Published online: 20 March 2008
Subject Categories:
The initiation factor eIF3-f is a major target for Atrogin1/MAFbx function in skeletal muscle atrophy
Julie Lagirand-Cantaloube1,2, Nicolas Offner1,23, Alfredo Csibi1, Marie P Leibovitch1, Sabrina Batonnet-Pichon1,4, Lionel A Tintignac1, Carlos T Segura1 and Serge A Leibovitch1
- Laboratoire de Génomique Fonctionnelle et Myogenèse, UMR866 Différenciation Cellulaire et Croissance, INRA UM II, Campus INRA/SUPAGRO, Montpellier, France
Correspondence to:
Serge A Leibovitch, UMR866 Différenciation Cellulaire et Croissance, INRA UM II, Campus INRA/SUPAGRO, 2 Place Pierre Viala, Montpellier Cedex 1 34060, France. Tel.: +33 04 99 61 29 76; Fax: +33 04 67 54 56 94; E-mail: leibovs@supagro.inra.fr
2These authors contributed equally to this work
3Present address: Département Génétique et Développement, INSERM U567, UMR-CNRS 8104, Institut Cochin, Paris 75014, France
4Present address: EA300, Stress et Pathologies du cytosquelette, Université Paris VII, 2 place Jussieu, Paris 75005, France
Received 12 July 2007; Accepted 25 February 2008
Abstract
In response to cancer, AIDS, sepsis and other systemic diseases inducing muscle atrophy, the E3 ubiquitin ligase Atrogin1/MAFbx (MAFbx) is dramatically upregulated and this response is necessary for rapid atrophy. However, the precise function of MAFbx in muscle wasting has been questioned. Here, we present evidence that during muscle atrophy MAFbx targets the eukaryotic initiation factor 3 subunit 5 (eIF3-f) for ubiquitination and degradation by the proteasome. Ectopic expression of MAFbx in myotubes induces atrophy and degradation of eIF3-f. Conversely, blockade of MAFbx expression by small hairpin RNA interference prevents eIF3-f degradation in myotubes undergoing atrophy. Furthermore, genetic activation of eIF3-f is sufficient to cause hypertrophy and to block atrophy in myotubes, whereas genetic blockade of eIF3-f expression induces atrophy in myotubes. Finally, eIF3-f induces increasing expression of muscle structural proteins and hypertrophy in both myotubes and mouse skeletal muscle. We conclude that eIF3-f is a key target that accounts for MAFbx function during muscle atrophy and has a major role in skeletal muscle hypertrophy. Thus, eIF3-f seems to be an attractive therapeutic target.
Keywords:
- Atrogin/MAFbx,
- atrophy,
- eIF3-f,
- hypertrophy,
- ubiquitin–proteasome
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