PSME4 Degrades Acetylated YAP1 in the Nucleus of Mesenchymal Stem Cells

Abstract

Intensive research has focused on minimizing the infarct area and stimulating endogenous regeneration after myocardial infarction. Our group previously elucidated that apicidin, a histone deacetylase (HDAC) inhibitor, robustly accelerates the cardiac commitment of naïve mesenchymal stem cells (MSCs) through acute loss of YAP1. Here, we propose the novel regulation of YAP1 in MSCs. We found that acute loss of YAP1 after apicidin treatment resulted in the mixed effects of transcriptional arrest and proteasomal degradation. Subcellular fractionation revealed that YAP1 was primarily localized in the cytoplasm. YAP1 was acutely relocalized into the nucleus and underwent proteasomal degradation. Interestingly, phosphor-S127 YAP1 was shuttled into the nucleus, suggesting that a mechanism other than phosphorylation governed the 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 26 S 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 acetylation-dependent proteasome subunit PSME4 clears acetyl-YAP1 in response to apicidin treatment in the nucleus of MSCs.

PSME4 determines mesenchymal stem cell fate towards cardiac commitment through YAP1 degradation

“…Although we demonstrated that nuclear PSME4 actively degraded acetyl-YAP1 in the nucleus in response to apicidin treatment [ 14 ], the fundamental role of PSME4 in the cardiac commitment of MSCs remains unclear. We isolated bone-marrow MSCs (BM-MSCs) from either Psme4 knock-out (KO) mice or wild-type littermates and tested the cellular characteristics of each genotypes.…”

“…1B–D ). When considering previous results [ 14 , 23 ], we assumed that the retardation of clearing of Yap1 in the nucleus was the responsible mechanism for delayed cardiac commitment. To answer the fundamental question, we employed the lentivirus-driven shRNA system in hTERT-MSCs.…”

“…It is also known that PSME4 target acetylated histone H3 for degradation, which can lead to changes in gene expression and cellular behavior in a proteasomal independent manner [ 13 ]. Besides, recent studies have shown that PSME4 plays a critical role in determining the fate of transcriptional co-activator YAP1 in the nucleus [ 14 ].…”

“…Our previous study demonstrated that apicidin, a class I histone deacetylase (HDAC) inhibitor, promotes cardiac commitment of MSCs [ 14 , 23 ], but the precise mechanism by which it occurs is not fully understood. We identified that the protein PSME4 recognizes and degrades acetylated-YAP1 in the nucleus during apicidin-dependent cardiac commitment.…”

The Proteasome Activator PA200/PSME4: An Emerging New Player in Health and Disease

“…Moreover, the two positively charged PA200 entry pores might not favor the binding of acetylated histones due to the predominance of positively charged histidine residues [ 4 , 9 , 10 ]. A very recent study showed that PA200 degrades acetylated-YAP1 in the in the nucleus of mesenchymal stem cells (MSC) in response to the histone deacetylase (HDAC) inhibitor apicidin [ 37 ]. The authors also injected PA200 KO MSCs into an infarcted heart to define the role of PA200 in myocardial infarction.…”