E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator.
E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator.
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DOI：
10.1126/science.aan3303
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发表时间：
2018-12-21
期刊：
影响因子：
--
通讯作者：
Song LS
中科院分区：
文献类型：
--
作者：
Guo A;Wang Y;Chen B;Wang Y;Yuan J;Zhang L;Hall D;Wu J;Shi Y;Zhu Q;Chen C;Thiel WH;Zhan X;Weiss RM;Zhan F;Musselman CA;Pufall M;Zhu W;Au KF;Hong J;Anderson ME;Grueter CE;Song LS
结膜亲蛋白2 （Junctophilin-2, JP2）是正常兴奋-收缩（E-C）耦合所必需的结构蛋白。在心脏应激后，JP2被Ca2+依赖性蛋白酶calpain切割，这破坏了E-C偶联的超微结构机制并驱动心力衰竭的进展。在这里，我们证明了应激诱导的JP2蛋白水解释放了一个n端片段（JP2NT），该片段易位到细胞核，与基因组DNA结合并控制心肌细胞中一系列基因的表达。JP2NT在小鼠中的转基因过表达改变了转录谱，导致心脏应激反应的病理重塑减弱。相反，JP2NT功能的丧失会加速突变小鼠应激诱导的肥厚和心力衰竭的发展。这些数据揭示了衰竭心肌细胞的自我保护机制，该机制将机械信息（E-C解偶联）转化为应激心脏中有益的转录重编程。JP2是一种对E-C偶联很重要的完整结构蛋白，含有一个保守的DNA结合域，调节转录途径并赋予心脏抵抗应激的保护作用。
Junctophilin-2 (JP2) is a structural protein required for normal excitation-contraction (E-C) coupling. Following cardiac stress, JP2 is cleaved by Ca2+-dependent protease calpain, which disrupts the E-C coupling ultrastructural machinery and drives heart failure progression. Here we demonstrate that stress-induced proteolysis of JP2 liberates an N-terminal fragment (JP2NT) that translocates to the nucleus, binds to genomic DNA and controls expression of a spectrum of genes in cardiomyocytes. Transgenic overexpression of JP2NT in mice modifies the transcriptional profile resulting in attenuated pathological remodeling in response to cardiac stress. Conversely, loss of JP2NT function accelerates stress-induced development of hypertrophy and heart failure in mutant mice. These data reveal a self-protective mechanism in failing cardiomyocytes that transduce mechanical information (E-C uncoupling) into salutary transcriptional reprogramming in the stressed heart. JP2, an integral structural protein important for E-C coupling, contains a conserved DNA binding domain that regulates transcriptional pathways and confers cardiac protection against stress.
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