Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Department of Emergency Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
Science. 2018 Dec 21;362(6421). doi: 10.1126/science.aan3303. Epub 2018 Nov 8.
Junctophilin-2 (JP2) is a structural protein required for normal excitation-contraction (E-C) coupling. After cardiac stress, JP2 is cleaved by the calcium ion-dependent protease calpain, which disrupts the E-C coupling ultrastructural machinery and drives heart failure progression. We found 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 nuclear 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.
连接蛋白-2 (JP2) 是一种正常兴奋-收缩 (E-C) 偶联所必需的结构蛋白。在心脏应激后，JP2 被钙依赖性蛋白酶钙蛋白酶切割，破坏 E-C 偶联超微结构机制，并推动心力衰竭的进展。我们发现，JP2 的应激诱导蛋白水解释放出一个 N 端片段 (JP2NT)，该片段转移到细胞核，与基因组 DNA 结合，并控制心肌细胞中一系列基因的表达。在小鼠中转基因过表达 JP2NT 会改变转录谱，从而减轻对心脏应激的病理性重塑反应。相反，核 JP2NT 功能缺失会加速突变小鼠应激诱导的肥大和心力衰竭的发展。这些数据揭示了衰竭心肌细胞中的一种自我保护机制，它将机械信息（E-C 解偶联）转化为应激心脏中的有益转录重编程。
