Science (New York, N.Y.) · 2018
E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
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Guo Ang, Wang Yihui, Chen Biyi, Wang Yunhao, Yuan Jinxiang, Zhang Liyang, Hall Duane, Wu Jennifer, Shi Yun, Zhu Qi, Chen Cheng, Thiel William H, Zhan Xin, Weiss Robert M, Zhan Fenghuang, Musselman Catherine A, Pufall Miles, Zhu Weizhong, Au Kin Fai, Hong Jiang, Anderson Mark E, Grueter Chad E, Song Long-Sheng
Аннотация
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.
Предметные рубрики MeSH
Active Transport, Cell NucleusAdaptation, PhysiologicalAnimalsCalpainCardiomegalyCell NucleusExcitation Contraction CouplingGene Expression RegulationHumansMEF2 Transcription FactorsMembrane ProteinsMiceMice, Inbred C57BLMice, TransgenicMuscle ProteinsMyocardial ContractionMyocytes, CardiacProteolysisTranscription, GeneticVentricular Remodeling