title: Acetylation of VGLL4 Regulates Hippo-YAP Signaling and Postnatal Cardiac Growth.
abstract: 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.
authors.affiliation: Department of Cardiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA. Electronic address: zlin@enders.tch.harvard.edu.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Lin
authors.affiliation: 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.
authors.forename: Haidong
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Cardiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA; Peking University, Fifth School of Clinical Medicine, Beijing 100730, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Cardiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Zohrabian
authors.affiliation: Department of Cardiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Pingzhu
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Department of Cardiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: VanDusen
authors.affiliation: Department of Cardiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Yuxuan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Cardiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Stevens
authors.affiliation: Rowland Institute at Harvard, Harvard University, Cambridge, MA 02142, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Liang
authors.affiliation: Rowland Institute at Harvard, Harvard University, Cambridge, MA 02142, USA.
authors.forename: Qimin
authors.initials: Q
authors.lastname: Quan
authors.affiliation: Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
authors.forename: Pim R
authors.initials: PR
authors.lastname: van Gorp
authors.affiliation: Department of Anatomy & Histology, Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Amy
authors.initials: A
authors.lastname: Li
authors.affiliation: Department of Anatomy & Histology, Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Cristobal
authors.initials: C
authors.lastname: Dos Remedios
authors.affiliation: Institute of Molecular Medicine, Peking University, PKU-Tsinghua U Joint Center for Life Sciences, Beijing 100871, China.
authors.forename: Aibin
authors.initials: A
authors.lastname: He
authors.affiliation: Department of Cardiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Vassilios J
authors.initials: VJ
authors.lastname: Bezzerides
authors.affiliation: Department of Cardiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address: wpu@pulab.org.
authors.forename: William T
authors.initials: WT
authors.lastname: Pu
mesh_terms: D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000375:Aging / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism; D006321:Heart / Q000254:growth & development*; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology; D000090683:Hippo Signaling Pathway; D006801:Humans; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D000072417:Protein Domains; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D055550:Protein Stability; D017208:Rats, Wistar; D015398:Signal Transduction; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D000091262:TEA Domain Transcription Factors; C083215:Tead1 protein, mouse; D014157:Transcription Factors; C000620724:VGLL4 protein, mouse; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: Hippo-YAP pathway; TEAD1; VGLL4; acetylation; cardiac; cardiomyocyte; degradation; necrosis; proliferation