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

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.