The Calcineurin-FoxO-MuRF1 signaling pathway regulates myofibril integrity in cardiomyocytes
The Calcineurin-FoxO-MuRF1 signaling pathway regulates myofibril integrity in cardiomyocytes
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DOI：
10.7554/elife.27955
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发表时间：
2017-08-19
期刊：
影响因子：
7.7
通讯作者：
Chen, Jau-Nian
中科院分区：
文献类型：
--
作者：
Shimizu, Hirohito;Langenbacher, Adam D.;Chen, Jau-Nian
钙离子处理的改变通常出现在结构重塑和功能恶化的疾病心脏中。然而，Ca~(2+)是否直接调节肌节结构仍不清楚。利用斑马鱼ncx1突变体，我们探讨了钙稳态受损对肌原纤维完整性的影响。我们发现E3泛素连接酶MuRF1在Ncx1缺陷的心脏中上调。有趣的是，下调MuRF1活性或抑制蛋白酶体活性可以保持肌原纤维的完整性，揭示了一种由MuRF1介导的蛋白酶体降解机制，该机制在响应异常的钙稳态时被激活。此外，我们检测到MuRF1调节因子FoxO在ncx1缺陷的心肌细胞的细胞核中积聚。FoxO在野生型心肌细胞中的过表达诱导了MuRF1的表达并导致肌原纤维的紊乱，而抑制钙调神经磷酸酶的活性则减弱了FoxO介导的MuRF1的表达，并保护了ncx1缺乏的心脏肌节的降解。总之，我们的发现揭示了一种新的机制，即钙超载通过激活钙调神经磷酸酶-FoxO-MuRF1-蛋白酶体信号通路来破坏肌原纤维的完整性。
Altered Ca2+ handling is often present in diseased hearts undergoing structural remodeling and functional deterioration. However, whether Ca2+ directly regulates sarcomere structure has remained elusive. Using a zebrafish ncx1 mutant, we explored the impacts of impaired Ca2+ homeostasis on myofibril integrity. We found that the E3 ubiquitin ligase murf1 is upregulated in ncx1-deficient hearts. Intriguingly, knocking down murf1 activity or inhibiting proteasome activity preserved myofibril integrity, revealing a MuRF1-mediated proteasome degradation mechanism that is activated in response to abnormal Ca2+ homeostasis. Furthermore, we detected an accumulation of the murf1 regulator FoxO in the nuclei of ncx1-deficient cardiomyocytes. Overexpression of FoxO in wild type cardiomyocytes induced murf1 expression and caused myofibril disarray, whereas inhibiting Calcineurin activity attenuated FoxO-mediated murf1 expression and protected sarcomeres from degradation in ncx1-deficient hearts. Together, our findings reveal a novel mechanism by which Ca2+ overload disrupts myofibril integrity by activating a Calcineurin-FoxO-MuRF1-proteosome signaling pathway.