Fig. 7. Model depicting the role of FBXO32 in the crosstalk between CHOP-dependent apoptosis and autophagy.

Mutation in the FBXO32 E3 ligase activates the ER stress response, which in turn induces the expression of CHOP protein. Increased CHOP expression activates the intrinsic-apoptosis pathway and induces GADD34 expression, which could amplify the apoptotic effect by promoting protein synthesis that leads to increased ER stress. The FBXO32 mutation increases ATF2 possibly increasing cell death. Together these molecular mechanisms amplify the maladaptive ER stress response and contribute to the development of heart failure. ER endoplasmic reticulum, DCM dilated cardiomyopathy.