Activating transcription factor 4 (ATF4) promotes skeletal muscle atrophy by forming a heterodimer with the transcriptional regulator C/EBP?
Activating transcription factor 4 (ATF4) promotes skeletal muscle atrophy by forming a heterodimer with the transcriptional regulator C/EBP?
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DOI：
10.1074/jbc.ra119.012095
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发表时间：
2020-02-28
影响因子：
4.8
通讯作者：
Adams, Christopher M.
中科院分区：
文献类型：
--
作者：
Ebert, Scott M.;Bullard, Steven A.;Adams, Christopher M.
骨骼肌萎缩是一种高度流行和衰弱的疾病，在分子水平上仍然知之甚少。先前的研究发现，衰老、禁食和制动通过骨骼肌纤维中转录激活因子4（ATF 4）的表达促进骨骼肌萎缩。然而，ATF4促进肌肉萎缩的直接生化机制尚不清楚。ATF4是碱性亮氨酸拉链转录因子（bZIP）超家族的成员。由于bZIP转录因子是专性二聚体，并且由于ATF 4不能形成高度稳定的同源二聚体，因此我们假设ATF 4可能通过与另一个bZIP家族成员形成异源二聚体来促进肌肉萎缩。为了验证这一假设，我们生化分离骨骼肌蛋白，与二聚化和DNA结合结构域的ATF4（bZIP域）在小鼠骨骼肌纤维在体内。有趣的是，我们发现ATF4在骨骼肌纤维中形成至少五种不同的异二聚体bZIP转录因子。此外，这些异二聚体，组成的ATF 4和CCAAT增强子结合蛋白？（C/EBP？），介导肌肉萎缩在骨骼肌纤维，ATF4？C/EBP？异源二聚体与以前未识别和进化保守的ATF相互作用？Gadd45a基因外显子4的C/EBP复合位点。ATF4、C/EBP？还有烟酒火器管理局C/EBP复合位点激活Gadd45a基因，该基因编码肌肉萎缩的关键介质。总之，这些结果确定了ATF4诱导骨骼肌萎缩的生化机制，为骨骼肌萎缩的病因学提供了分子水平的见解。
Skeletal muscle atrophy is a highly-prevalent and debilitating condition that remains poorly understood at the molecular level. Previous work found that aging, fasting, and immobilization promote skeletal muscle atrophy via expression of activating transcription factor 4 (ATF4) in skeletal muscle fibers. However, the direct biochemical mechanism by which ATF4 promotes muscle atrophy is unknown. ATF4 is a member of the basic leucine zipper transcription factor (bZIP) superfamily. Because bZIP transcription factors are obligate dimers, and because ATF4 is unable to form highly-stable homodimers, we hypothesized that ATF4 may promote muscle atrophy by forming a heterodimer with another bZIP family member. To test this hypothesis, we biochemically isolated skeletal muscle proteins that associate with the dimerization- and DNA-binding domain of ATF4 (the bZIP domain) in mouse skeletal muscle fibers in vivo. Interestingly, we found that ATF4 forms at least five distinct heterodimeric bZIP transcription factors in skeletal muscle fibers. Furthermore, one of these heterodimers, composed of ATF4 and CCAAT enhancer-binding protein ? (C/EBP?), mediates muscle atrophy. Within skeletal muscle fibers, the ATF4?C/EBP? heterodimer interacts with a previously unrecognized and evolutionarily conserved ATF?C/EBP composite site in exon 4 of the Gadd45a gene. This three-way interaction between ATF4, C/EBP?, and the ATF?C/EBP composite site activates the Gadd45a gene, which encodes a critical mediator of muscle atrophy. Together, these results identify a biochemical mechanism by which ATF4 induces skeletal muscle atrophy, providing molecular-level insights into the etiology of skeletal muscle atrophy.