EIF4E2 Mediates RBM24 Phosphorylation Underlying Cardiac Adaptation To Stress

Epidemiological studies have shown that there is a close relationship between psychological stress and cardiovascular disease,but the molecular mechanism remains unclear.RBM24 is a heart-specific RNA-binding protein that affects early cardiac development by regulating mRNA splicing and protein translation.The function of RBM24 in heart disease is unclear.We explored the mechanism of RBM24 in the occurrence of heart disease and carried out the following studies:1)We found that acute stress and chronic stress activate RBM24 S181 phosphorylation via GSK3β.We successfully constructed RBM24 S181A knock-in mutant mice.We found that acute stress resulted in decreased exercise capacity and cardiac damage in RBM24 S181A mutant mice.ECG results showed that short-term stress caused S181A mutant mice to develop atrial fibrillation,the most common clinical arrhythmia associated with stroke and heart failure.2)Under chronic stress,RBM24 S181A mutant mice developed cardiac systolic dysfunction,decreased left ventricular ejection fraction(LVEF)and left ventricular short-axis shortening(LVFS),and developed cardiac fibrosis.Hearts of RBM24 S181A mutant mice develop fibrosis under chronic unpredictable fear stress(UFS).3)We found that eIF4E2 bidirectionally regulates S181 phosphorylation as a translation initiation factor in response to hypoxia.On the one hand,stress activates RBM24 S181 phosphorylation through the hypoxia-dependent eIF4E2-GSK3β pathway.Meanwhile,the N-terminus of eIF4E2 interacted with RBM24 to directly inhibit S181 phosphorylation.Furthermore,we found that the β2-adrenoceptor directly interacts with eIF4E2 to mediate stress signaling to the heart.4)RBM24 S181 phosphorylation regulates protein translation.Under acute stress,RBM24 S181 phosphorylation directly regulates p53 and CHRM2 protein translation.Through translation group analysis,it was further found that phosphorylation of RBM24 S181 directly regulates the translation of ApoE protein.RBM24 S181 point mutant mice exhibit higher cholesterol levels under chronic stress due to ApoE translational inhibition,mediating cardiac fibrosis.Simvastatin,a clinical drug for the treatment of cardiovascular disease,can prevent the occurrence of cardiac fibrosis in RBM24 S181 point mutant mice under stressful conditions by removing cholesterol from the body.5)We developed the nanobody Nb.30G11 that can directly inhibit the RBM24/eIF4E2 interaction,thereby activating S181 phosphorylation to protect the heart from stress.Stress-induced phosphorylation of RBM24 S181 can be released into the serum of mice,rats and rabbits.Further,in healthy adults between the ages of 25 and 45,phosphorylation of RBM24 S181 was also activated and released into serum after a short period of social isolation.Therefore,RBM24 S181 phosphorylation may serve as a diagnostic marker for stress or stress-related cardiac disease.In conclusion,we reveal the unique regulatory mechanism that phosphorylation of RBM24 S181 mediates the close relationship between mental stress and heart disease,and preliminarily demonstrate that mental stress-induced heart disease can be prevented.