G3BP1 Succinylation at K413 is Critical for Cardiac Function by Modulating PI3K‐AKT‐mTOR Signal Axis

G3BP1, GTPase activating protein (SH3 domain) binding protein 1, is a core component of stress granules. Homozygous null mutations in the G3bp1 gene result in embryonic lethality, underscoring its essential role in development. While various post-translational modifications regulate G3BP1 activity, here we first report that G3BP1 undergoes succinylation (Suc) at Lys (K)411 in mouse hearts (corresponding to human K413). G3BP1-Suc level was diminished in Myosin binding protein C3 (Mybpc3) knockout and transverse aortic constriction (TAC) operated mice, which developed heart failure (HF). Site-directed mutagenesis confirmed that the K413R mutation compromised the overall Suc level of G3BP1 in vitro. Mice injected with AAV9-G3BP1 (WT) developed typical phenotypes of dilated cardiomyopathy (DCM) and HF when compared to mice injected with AAV9-Ctrl and -G3BP1 (K411R) mice, suggesting a possible loss of functional effect of de-Suc at K411. Moreover, Homozygous knock-in G3bp1 (K411R) mice exhibited compromised cardiac parameters compared to WT littermates. De novo G3BP1 mutation (p.E411G) from a DCM patient disrupts Suc at K413. Mechanistically, G3BP1 de-Suc at K413 induced Rraga expression and impaired TSC1/2 and IDE binding, ultimately leading to excessive activation of the PI3K-AKT-mTOR signaling axis. We demonstrate a critical role for G3BP1 Suc at K413 in cardiac function by modulating the PI3K-AKT-mTOR pathway, providing new insights into the non-canonical function of G3BP1 in cardiomyopathy and HF pathogenesis.