Lin Zhiqiang, Guo Haidong, Cao Yuan, Zohrabian Sylvia, Zhou Pingzhu, Ma Qing, VanDusen Nathan, Guo Yuxuan, Zhang Jin, Stevens Sean M, Liang Feng, Quan Qimin, van Gorp Pim R, Li Amy, Dos Remedios Cristobal, He Aibin, Bezzerides Vassilios J, Pu William T
Department of Cardiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
Department of Cardiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Dev Cell. 2016 Nov 21;39(4):466-479. doi: 10.1016/j.devcel.2016.09.005. Epub 2016 Oct 6.
Binding of the transcriptional co-activator YAP with the transcription factor TEAD stimulates growth of the heart and other organs. YAP overexpression potently stimulates fetal cardiomyocyte (CM) proliferation, but YAP's mitogenic potency declines postnatally. While investigating factors that limit YAP's postnatal mitogenic activity, we found that the CM-enriched TEAD1 binding protein VGLL4 inhibits CM proliferation by inhibiting TEAD1-YAP interaction and by targeting TEAD1 for degradation. Importantly, VGLL4 acetylation at lysine 225 negatively regulated its binding to TEAD1. This developmentally regulated acetylation event critically governs postnatal heart growth, since overexpression of an acetylation-refractory VGLL4 mutant enhanced TEAD1 degradation, limited neonatal CM proliferation, and caused CM necrosis. Our study defines an acetylation-mediated, VGLL4-dependent switch that regulates TEAD stability and YAP-TEAD activity. These insights may improve targeted modulation of TEAD-YAP activity in applications from cardiac regeneration to cancer.
转录共激活因子YAP与转录因子TEAD的结合会刺激心脏和其他器官的生长。YAP的过表达能有效刺激胎儿心肌细胞（CM）增殖，但YAP的促有丝分裂能力在出生后会下降。在研究限制YAP出生后促有丝分裂活性的因素时，我们发现富含CM的TEAD1结合蛋白VGLL4通过抑制TEAD1-YAP相互作用以及靶向降解TEAD1来抑制CM增殖。重要的是，赖氨酸225处的VGLL4乙酰化负向调节其与TEAD1的结合。这种受发育调控的乙酰化事件对出生后心脏生长至关重要，因为乙酰化抗性VGLL4突变体的过表达增强了TEAD1降解，限制了新生CM增殖，并导致CM坏死。我们的研究定义了一种乙酰化介导的、依赖VGLL4的开关，该开关调节TEAD稳定性和YAP-TEAD活性。这些见解可能会改善从心脏再生到癌症等应用中对TEAD-YAP活性的靶向调节。
