Ser14 phosphorylation of Bcl-xL mediates compensatory cardiac hypertrophy in male mice
Abstract The anti-apoptotic function of Bcl-xL in the heart during ischemia/reperfusion is diminished by K-Ras-Mst1-mediated phosphorylation of Ser14, which allows dissociation of Bcl-xL from Bax and promotes cardiomyocyte death. Here we show that Ser14 phosphorylation of Bcl-xL is also promoted by...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-41595-x |
| _version_ | 1797558474266116096 |
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| author | Michinari Nakamura Mariko Aoyagi Keller Nadezhda Fefelova Peiyong Zhai Tong Liu Yimin Tian Shohei Ikeda Dominic P. Del Re Hong Li Lai-Hua Xie Junichi Sadoshima |
| author_facet | Michinari Nakamura Mariko Aoyagi Keller Nadezhda Fefelova Peiyong Zhai Tong Liu Yimin Tian Shohei Ikeda Dominic P. Del Re Hong Li Lai-Hua Xie Junichi Sadoshima |
| author_sort | Michinari Nakamura |
| collection | DOAJ |
| description | Abstract The anti-apoptotic function of Bcl-xL in the heart during ischemia/reperfusion is diminished by K-Ras-Mst1-mediated phosphorylation of Ser14, which allows dissociation of Bcl-xL from Bax and promotes cardiomyocyte death. Here we show that Ser14 phosphorylation of Bcl-xL is also promoted by hemodynamic stress in the heart, through the H-Ras-ERK pathway. Bcl-xL Ser14 phosphorylation-resistant knock-in male mice develop less cardiac hypertrophy and exhibit contractile dysfunction and increased mortality during acute pressure overload. Bcl-xL Ser14 phosphorylation enhances the Ca2+ transient by blocking the inhibitory interaction between Bcl-xL and IP3Rs, thereby promoting Ca2+ release and activation of the calcineurin-NFAT pathway, a Ca2+-dependent mechanism that promotes cardiac hypertrophy. These results suggest that phosphorylation of Bcl-xL at Ser14 in response to acute pressure overload plays an essential role in mediating compensatory hypertrophy by inducing the release of Bcl-xL from IP3Rs, alleviating the negative constraint of Bcl-xL upon the IP3R-NFAT pathway. |
| first_indexed | 2024-03-10T17:31:56Z |
| format | Article |
| id | doaj.art-b9bfcd040f214f66aef8605328265d08 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:31:56Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-b9bfcd040f214f66aef8605328265d082023-11-20T10:00:02ZengNature PortfolioNature Communications2041-17232023-09-0114111510.1038/s41467-023-41595-xSer14 phosphorylation of Bcl-xL mediates compensatory cardiac hypertrophy in male miceMichinari Nakamura0Mariko Aoyagi Keller1Nadezhda Fefelova2Peiyong Zhai3Tong Liu4Yimin Tian5Shohei Ikeda6Dominic P. Del Re7Hong Li8Lai-Hua Xie9Junichi Sadoshima10Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical SchoolDepartment of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical SchoolDepartment of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical SchoolDepartment of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical SchoolCenter for Advanced Proteomics Research, Department of Biochemistry & Molecular Biology, Rutgers New Jersey Medical SchoolDepartment of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical SchoolDepartment of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical SchoolDepartment of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical SchoolCenter for Advanced Proteomics Research, Department of Biochemistry & Molecular Biology, Rutgers New Jersey Medical SchoolDepartment of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical SchoolDepartment of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical SchoolAbstract The anti-apoptotic function of Bcl-xL in the heart during ischemia/reperfusion is diminished by K-Ras-Mst1-mediated phosphorylation of Ser14, which allows dissociation of Bcl-xL from Bax and promotes cardiomyocyte death. Here we show that Ser14 phosphorylation of Bcl-xL is also promoted by hemodynamic stress in the heart, through the H-Ras-ERK pathway. Bcl-xL Ser14 phosphorylation-resistant knock-in male mice develop less cardiac hypertrophy and exhibit contractile dysfunction and increased mortality during acute pressure overload. Bcl-xL Ser14 phosphorylation enhances the Ca2+ transient by blocking the inhibitory interaction between Bcl-xL and IP3Rs, thereby promoting Ca2+ release and activation of the calcineurin-NFAT pathway, a Ca2+-dependent mechanism that promotes cardiac hypertrophy. These results suggest that phosphorylation of Bcl-xL at Ser14 in response to acute pressure overload plays an essential role in mediating compensatory hypertrophy by inducing the release of Bcl-xL from IP3Rs, alleviating the negative constraint of Bcl-xL upon the IP3R-NFAT pathway.https://doi.org/10.1038/s41467-023-41595-x |
| spellingShingle | Michinari Nakamura Mariko Aoyagi Keller Nadezhda Fefelova Peiyong Zhai Tong Liu Yimin Tian Shohei Ikeda Dominic P. Del Re Hong Li Lai-Hua Xie Junichi Sadoshima Ser14 phosphorylation of Bcl-xL mediates compensatory cardiac hypertrophy in male mice Nature Communications |
| title | Ser14 phosphorylation of Bcl-xL mediates compensatory cardiac hypertrophy in male mice |
| title_full | Ser14 phosphorylation of Bcl-xL mediates compensatory cardiac hypertrophy in male mice |
| title_fullStr | Ser14 phosphorylation of Bcl-xL mediates compensatory cardiac hypertrophy in male mice |
| title_full_unstemmed | Ser14 phosphorylation of Bcl-xL mediates compensatory cardiac hypertrophy in male mice |
| title_short | Ser14 phosphorylation of Bcl-xL mediates compensatory cardiac hypertrophy in male mice |
| title_sort | ser14 phosphorylation of bcl xl mediates compensatory cardiac hypertrophy in male mice |
| url | https://doi.org/10.1038/s41467-023-41595-x |
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