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G3BP1 Succinylation at K413 is Critical for Cardiac Function by Modulating PI3K-AKT-mTOR Signal Axis.
Yuan Zhang1, Cancan Yao2, Yan Chen2
1Shanghai Key Laboratory of Maternal Fetal Medicine, Center for Assisted Reproduction, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
Summary
GTPase activating protein (SH3 domain) binding protein 1 (G3BP1) succinylation at Lys413 is crucial for heart function. Loss of this modification in G3BP1 leads to cardiomyopathy and heart failure by activating the PI3K-AKT-mTOR pathway.
Area of Science:
- Biochemistry
- Molecular Biology
- Cardiovascular Research
Background:
- GTPase activating protein (SH3 domain) binding protein 1 (G3BP1) is essential for development and a stress granule component.
- Post-translational modifications regulate G3BP1 activity, but its succinylation in the heart was previously uncharacterized.
Purpose of the Study:
- To investigate the role of G3BP1 succinylation in cardiac function and heart failure pathogenesis.
- To identify the specific site of G3BP1 succinylation and its functional consequences.
Main Methods:
- Site-directed mutagenesis to create G3BP1 K411R and K413R variants.
- Adeno-associated virus 9 (AAV9) delivery of wild-type and mutant G3BP1 in mice.
- Generation of homozygous knock-in G3bp1 (K411R) mice.
- Analysis of cardiac parameters, protein binding, gene expression, and signaling pathways.
Main Results:
- G3BP1 succinylation at Lys411 (mouse) / Lys413 (human) was identified in the heart.
- G3BP1 succinylation levels decreased in models of heart failure (Mybpc3 knockout, TAC).
- G3BP1 K411R mutation and de-succinylation impaired cardiac function, leading to dilated cardiomyopathy and heart failure phenotypes.
- De-succinylation at K413 induced Rraga, impaired TSC1/2 and IDE binding, and activated the PI3K-AKT-mTOR pathway.
Conclusions:
- G3BP1 succinylation at Lys413 is critical for maintaining normal cardiac function.
- Disruption of G3BP1 succinylation contributes to cardiomyopathy and heart failure.
- G3BP1's role in heart disease involves modulation of the PI3K-AKT-mTOR signaling pathway.
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