FICD (FIC Domain Protein Adenylyl Transferase) Deficiency Protects Mice From Hypertrophy-Induced Heart Failure and Promotes BiP (Binding Immunoglobulin Protein) -Mediated Activation of the Unfolded Protein Response and Endoplasmic Reticulum-Selective Autophagy in Cardiomyocytes.

BACKGROUND: Cardiomyocytes require the HSP70 (heat shock protein 70) chaperone BiP (binding immunoglobulin protein) to maintain proteostasis in the endoplasmic reticulum (ER) following cardiac stress. The adenylyl transferase FICD (FIC domain protein adenylyl transferase) is increasingly recognized to regulate BiP activity through the posttranslational addition of an adenosine monophosphate moiety to BiP surface residues. However, the physiological impact of FICD-mediated BiP regulation in the context of cardiovascular health is unknown. METHODS: We assessed 6-month and 12-month-old wild-type and FICD knockout mice in a transverse aortic constriction hypertrophy paradigm. We determined cardiac function and injury using echocardiography, histological stainings, and biochemical approaches. In complementary assays, we used isolated neonatal wild-type and FICD knockout cardiomyocytes and cardiac fibroblasts to quantitatively assess cell-type specific adaptations in proteostasis and ER stress responses. RESULTS: We find that FICD deficiency prevents pressure overload-associated heart failure, hypertrophy, and fibrosis. At a cellular level, we observe that FICD-mediated BiP AMPylation blunts the induction of the unfolded protein response and impairs BiP interaction with FAM134B, an ER-selective autophagy receptor, thus limiting ER-selective autophagy induction under stress. In contrast, FICD loss significantly increases BiP-dependent unfolded protein response induction and ER-selective autophagy in stressed cardiomyocytes. We also uncover cell type-specific consequences of FICD activity in response to ER stress, positioning FICD as a critical proteostasis regulator in cardiac tissue. CONCLUSIONS: Our results highlight a novel regulatory paradigm controlling stress resilience in cardiomyocytes and offer a rationale to consider FICD as a therapeutic target to treat cardiac hypertrophy.