Ser14 phosphorylation of Bcl-xL mediates compensatory cardiac hypertrophy in male mice

Michinari Nakamura (), Mariko Aoyagi Keller, Nadezhda Fefelova, Peiyong Zhai, Tong Liu, Yimin Tian, Shohei Ikeda, Dominic P. Re, Hong Li, Lai-Hua Xie and Junichi Sadoshima ()
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Michinari Nakamura: Rutgers-New Jersey Medical School
Mariko Aoyagi Keller: Rutgers-New Jersey Medical School
Nadezhda Fefelova: Rutgers-New Jersey Medical School
Peiyong Zhai: Rutgers-New Jersey Medical School
Tong Liu: Rutgers New Jersey Medical School
Yimin Tian: Rutgers-New Jersey Medical School
Shohei Ikeda: Rutgers-New Jersey Medical School
Dominic P. Re: Rutgers-New Jersey Medical School
Hong Li: Rutgers New Jersey Medical School
Lai-Hua Xie: Rutgers-New Jersey Medical School
Junichi Sadoshima: Rutgers-New Jersey Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41595-x

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