Abstract P1135: Psme4 Degrades Acetylated Yap1 In The Nucleus Of Mesenchymal Stem Cells To Induce Cardiac Commitment
Circulation Research(2022)
Abstract
Intensive research has focused on minimizing the infarct area and stimulating endogenous regeneration after myocardial infarction. Our group elucidated that apicidin, a histone deacetylase (HDAC) inhibitor, robustly stimulates cardiac commitment of mesenchymal stem cells (MSCs) through acute loss of YAP1. Here we further studied the mechanism of this role of YAP1 in MSCs. We found that acute loss of YAP1 after apicidin treatment resulted in the mixed effects of transcriptional arrest and proteosomal degradation. Subcellular fractionation revealed that YAP1 was primarily localized in the cytoplasm. YAP1 was acutely relocalized into the nucleus and underwent proteosomal degradation. Interestingly, phosphor-S127 YAP1 was shuttled into the nucleus, suggesting that a mechanism other than phosphorylation governed subcellular localization of YAP1. Apicidin successfully induced acetylation and subsequent dissociation of YAP1 from 14-3-3, an essential molecule for cytoplasmic restriction. HDAC6 regulated both acetylation and subcellular localization of YAP1. An acetylation-dead mutant of YAP1 retarded nuclear redistribution upon apicidin treatment. We failed to acquire convincing evidence for polyubiquitination-dependent degradation of YAP1, suggesting that a polyubiquitination-independent regulator determined YAP1 fate. Nuclear PSME4, a subunit of the 26S proteasome, recognized and degraded acetyl YAP1 in the nucleus. MSCs from PSME4-null mice were injected into infarcted heart and aberrant sudden death was observed. Injection of immortalized human MSCs after knocking down PSME4 failed to improve either cardiac function or the fibrotic scar area. Our data suggest that acute ablation of YAP1 in the nucleus by the acetylation-dependent proteasome subunit PSME4 is mandatory for cardiac commitment of MSCs.
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Key words
psme4 degrades acetylated yap1,mesenchymal stem cells,cardiac,nucleus
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