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The initiation factor eIF3-f is a major target for atrogin1/MAFbx function in skeletal muscle atrophy.
- Source :
-
The EMBO journal [EMBO J] 2008 Apr 23; Vol. 27 (8), pp. 1266-76. Date of Electronic Publication: 2008 Mar 20. - Publication Year :
- 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.
- Subjects :
- Animals
Cell Line
Disease Models, Animal
Female
Humans
Hypertrophy enzymology
Hypertrophy metabolism
Mice
Mice, Inbred C57BL
Muscle Fibers, Skeletal enzymology
Muscle Fibers, Skeletal metabolism
Muscle Fibers, Skeletal pathology
Muscle, Skeletal enzymology
Muscular Atrophy enzymology
Proteasome Endopeptidase Complex metabolism
Proteasome Endopeptidase Complex physiology
Protein Interaction Mapping
Ubiquitination
Eukaryotic Initiation Factor-3 metabolism
Muscle Proteins physiology
Muscle, Skeletal metabolism
Muscle, Skeletal pathology
Muscular Atrophy metabolism
Muscular Atrophy pathology
SKP Cullin F-Box Protein Ligases physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2075
- Volume :
- 27
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- The EMBO journal
- Publication Type :
- Academic Journal
- Accession number :
- 18354498
- Full Text :
- https://doi.org/10.1038/emboj.2008.52