2. Academic Validation
  3. YAP K236 acetylation facilitates its nucleic export and deprived the protection against cardiac hypertrophy in mice

YAP K236 acetylation facilitates its nucleic export and deprived the protection against cardiac hypertrophy in mice

  • Pharmacol Res. 2025 Jan:211:107573. doi: 10.1016/j.phrs.2024.107573.
Panxia Wang 1,  Luping Wang 1,  Cui Liu 2,  Yuehuai Hu 2,  Guodong Feng 2,  Zuqian Lian 1,  Jing Lu 2,  Ping He 3,  Hexin Cai 1,  Xiaohui Liang 4,  Peiqing Liu 5,  Xiaoqian Wu 6
Affiliations

Affiliations

  • 1 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, PR China.
  • 2 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
  • 3 Department of Pharmacy, The Eighth Affiliated Hospital, Sun Yat-sen University, Shennan Rord 3025, Shenzhen 518033, PR China.
  • 4 The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 511436, PR China.
  • 5 Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, PR China; Guangdong Provincial Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou 510006, PR China. Electronic address: liupq@mail.sysu.edu.cn.
  • 6 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, PR China. Electronic address: wuxiaoqian@gzhmu.edu.cn.
PMID: 39746498 DOI: 10.1016/j.phrs.2024.107573
Abstract

The subcellular localization of Yes-associated protein (YAP) is dynamically regulated by post-transcriptional modifications, critically influencing cardiac function. Despite its significance, the precise mechanism controlling YAP nuclear sequestration and its role in cardiac hypertrophy remain poorly defined. In this study, utilizing immunoprecipitation-mass spectrometry, we identified potential acetylation sites and interacting proteins of YAP. Co-immunoprecipitation and immunofluorescence assays were used to elucidate the protein interactions and subcellular colocalization. We found that YAP protected against ISO-induced pathological cardiac hypertrophy both in vivo and in vitro. During cardiac hypertrophy YAP acetylation increased while its nuclear accumulation reduced without altering Ser127 phosphorylation. Notably, lysine 236 was identified as a novel acetylation site on YAP. Acetylation at K236 facilitated YAP's nucleic export, suppressed the expression of target genes such as NRF1 and COX IV, and counteracted YAP's anti-hypertrophic effects. Importantly, deacetylase SIRT6 was identified as a regulator of YAP deacetylation, disrupting the YAP with chaperone protein 14-3-3 interaction and inhibiting YAP's nuclear export, thereby facilitating cardiac protective role of YAP. This study identified YAP K236 acetylation as a key regulator of its nuclear retention in cardiomyocytes, with SIRT6-mediated deacetylation facilitating YAP's protective effects against cardiac hypertrophy. Targeting YAP acetylation may offer a promising therapeutic strategy for cardiac hypertrophy.

Keywords

Acetylation; Cardiac hypertrophy; K236 residues; SIRT6; YAP.

Figures
Products