PSME4 Degrades Acetylated YAP1 in the Nucleus of Mesenchymal Stem Cells
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)...
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MDPI AG
2022-08-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/8/1659 |
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| author | Yong Sook Kim Mira Kim Dong Im Cho Soo Yeon Lim Ju Hee Jun Mi Ra Kim Bo Gyeong Kang Gwang Hyeon Eom Gaeun Kang Somy Yoon Youngkeun Ahn |
| author_facet | Yong Sook Kim Mira Kim Dong Im Cho Soo Yeon Lim Ju Hee Jun Mi Ra Kim Bo Gyeong Kang Gwang Hyeon Eom Gaeun Kang Somy Yoon Youngkeun Ahn |
| author_sort | Yong Sook Kim |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T09:50:35Z |
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| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T09:50:35Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-0cf339f8e6404a4faff4e0bc7c2b714e2023-12-02T00:09:58ZengMDPI AGPharmaceutics1999-49232022-08-01148165910.3390/pharmaceutics14081659PSME4 Degrades Acetylated YAP1 in the Nucleus of Mesenchymal Stem CellsYong Sook Kim0Mira Kim1Dong Im Cho2Soo Yeon Lim3Ju Hee Jun4Mi Ra Kim5Bo Gyeong Kang6Gwang Hyeon Eom7Gaeun Kang8Somy Yoon9Youngkeun Ahn10Biomedical Research Institute, Chonnam National University Hospital, Gwangju 61469, KoreaDepartment of Pharmacology, Chonnam National University Medical School, Hwasun 58128, KoreaBiomedical Research Institute, Chonnam National University Hospital, Gwangju 61469, KoreaBiomedical Research Institute, Chonnam National University Hospital, Gwangju 61469, KoreaBiomedical Research Institute, Chonnam National University Hospital, Gwangju 61469, KoreaBiomedical Research Institute, Chonnam National University Hospital, Gwangju 61469, KoreaBiomedical Research Institute, Chonnam National University Hospital, Gwangju 61469, KoreaDepartment of Pharmacology, Chonnam National University Medical School, Hwasun 58128, KoreaDivision of Clinical Pharmacology, Chonnam National University Hospital, Gwangju 61469, KoreaCollege of Pharmacy, Chonnam National University, Gwangju 61186, KoreaDepartment of Cardiology, Chonnam National University Hospital, Gwangju 61469, KoreaIntensive 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.https://www.mdpi.com/1999-4923/14/8/1659mesenchymal stem cellacetylationYAP1PSME4 |
| spellingShingle | Yong Sook Kim Mira Kim Dong Im Cho Soo Yeon Lim Ju Hee Jun Mi Ra Kim Bo Gyeong Kang Gwang Hyeon Eom Gaeun Kang Somy Yoon Youngkeun Ahn PSME4 Degrades Acetylated YAP1 in the Nucleus of Mesenchymal Stem Cells Pharmaceutics mesenchymal stem cell acetylation YAP1 PSME4 |
| title | PSME4 Degrades Acetylated YAP1 in the Nucleus of Mesenchymal Stem Cells |
| title_full | PSME4 Degrades Acetylated YAP1 in the Nucleus of Mesenchymal Stem Cells |
| title_fullStr | PSME4 Degrades Acetylated YAP1 in the Nucleus of Mesenchymal Stem Cells |
| title_full_unstemmed | PSME4 Degrades Acetylated YAP1 in the Nucleus of Mesenchymal Stem Cells |
| title_short | PSME4 Degrades Acetylated YAP1 in the Nucleus of Mesenchymal Stem Cells |
| title_sort | psme4 degrades acetylated yap1 in the nucleus of mesenchymal stem cells |
| topic | mesenchymal stem cell acetylation YAP1 PSME4 |
| url | https://www.mdpi.com/1999-4923/14/8/1659 |
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