The initiation factor eIF3-f is a major target for Atrogin1/MAFbx function in skeletal muscle atrophy
The initiation factor eIF3-f is a major target for Atrogin1/MAFbx function in skeletal muscle atrophy
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DOI：
10.1038/emboj.2008.52
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发表时间：
2008-04-23
期刊：
影响因子：
11.4
通讯作者：
Leibovitch, Serge A.
中科院分区：
文献类型：
--
作者：
Lagirand-Cantaloube, Julie;Offner, Nicolas;Leibovitch, Serge A.
在对癌症、AIDS、脓毒症和其他诱导肌肉萎缩的全身性疾病的反应中，E3泛素连接酶Atrogin 1/MAFbx（MAFbx）显著上调，并且这种反应是快速萎缩所必需的。然而，MAFbx在肌肉萎缩中的确切功能受到质疑。在这里，我们提出的证据表明，在肌肉萎缩MAFbx靶向真核起始因子3亚基5（eIF 3-f）的泛素化和降解的蛋白酶体。肌管中MAFbx的异位表达诱导eIF 3-f的萎缩和降解。相反，通过小发夹RNA干扰阻断MAFbx表达可防止发生萎缩的肌管中eIF 3-f降解。此外，eIF 3-f的遗传激活足以引起肌管肥大并阻断肌管萎缩，而eIF 3-f表达的遗传阻断诱导肌管萎缩。最后，eIF 3-f诱导肌管和小鼠骨骼肌中肌肉结构蛋白的表达增加和肥大。我们得出结论，eIF 3-f是一个关键的目标，占MAFbx功能在肌肉萎缩和骨骼肌肥大的主要作用。因此，eIF 3-f似乎是一个有吸引力的治疗靶点。
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.