Gadd45a Protein Promotes Skeletal Muscle Atrophy by Forming a Complex with the Protein Kinase MEKK4.
Gadd45a Protein Promotes Skeletal Muscle Atrophy by Forming a Complex with the Protein Kinase MEKK4.
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DOI：
10.1074/jbc.m116.740308
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发表时间：
2016-08-19
期刊：
影响因子：
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通讯作者：
Adams CM
中科院分区：
文献类型：
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作者：
Bullard SA;Seo S;Schilling B;Dyle MC;Dierdorff JM;Ebert SM;DeLau AD;Gibson BW;Adams CM
骨骼肌萎缩是一种严重且高度流行的疾病，在分子水平上仍知之甚少。以前的工作发现，骨骼肌萎缩涉及骨骼肌Gadd45a表达的增加，这是骨骼肌纤维萎缩所必需的，也是充分的。然而，Gadd45a促进骨骼肌萎缩的直接机制尚不清楚。为了解决这个问题，我们生化分离了与Gadd45a相关的骨骼肌蛋白，因为Gadd45a在体内诱导小鼠骨骼肌纤维萎缩。我们发现Gadd45a与骨骼肌纤维中的多种蛋白质相互作用，其中最突出的是MEKK4，这是一种丝裂原激活的蛋白激酶，以前并不知道在骨骼肌萎缩中发挥作用。此外，我们发现，通过与骨骼肌纤维中的MEKK4形成复合体，Gadd45a增加了MEKK4蛋白激酶的活性，这既足以诱导骨骼肌纤维萎缩，也是Gadd45a介导的骨骼肌纤维萎缩所必需的。总之，这些结果确定了Gadd45a诱导骨骼肌萎缩的直接生化机制，并为在分子水平上了解骨骼肌萎缩的发生方式提供了新的见解。
Skeletal muscle atrophy is a serious and highly prevalent condition that remains poorly understood at the molecular level. Previous work found that skeletal muscle atrophy involves an increase in skeletal muscle Gadd45a expression, which is necessary and sufficient for skeletal muscle fiber atrophy. However, the direct mechanism by which Gadd45a promotes skeletal muscle atrophy was unknown. To address this question, we biochemically isolated skeletal muscle proteins that associate with Gadd45a as it induces atrophy in mouse skeletal muscle fibers in vivo. We found that Gadd45a interacts with multiple proteins in skeletal muscle fibers, including, most prominently, MEKK4, a mitogen-activated protein kinase kinase kinase that was not previously known to play a role in skeletal muscle atrophy. Furthermore, we found that, by forming a complex with MEKK4 in skeletal muscle fibers, Gadd45a increases MEKK4 protein kinase activity, which is both sufficient to induce skeletal muscle fiber atrophy and required for Gadd45a-mediated skeletal muscle fiber atrophy. Together, these results identify a direct biochemical mechanism by which Gadd45a induces skeletal muscle atrophy and provide new insight into the way that skeletal muscle atrophy occurs at the molecular level.