ArticleJournal of the American Heart Association2025
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.
Article in Journal of the American Heart Association, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Profiling of Yeast Saccharomyces cerevisiae Mitochondrial AMPylome Reveals a Regulation of OXPHOS Coupling through ATP Synthase Subunit Delta.Journal of proteome research · 2026Article
- Inhibition of FicD-mediated AMPylation and deAMPylation by isoprenoid diphosphates.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Increased FICD-mediated protein AMPylation triggers conserved endoplasmic reticulum stress signaling across species.Cell stress & chaperones · 2026Article
- Functionally diversified Caenorhabditis elegans BiP orthologs control body growth, reproduction, stress resistance, aging, and autophagy.Nature communications · 2025Article
- Loss of FIC-1-mediated AMPylation activates the UPRER and upregulates cytosolic HSP70 chaperones to suppress polyglutamine toxicity.PLoS genetics · 2025Article
- Small-Molecule FICD Inhibitors Suppress Endogenous and Pathologic FICD-Mediated Protein AMPylation.ACS chemical biology · 2025Article
- The multifaceted role of autophagy and mitophagy in cardiovascular health and disease.Autophagy reports · 2025Review
- Small molecule FICD inhibitors suppress endogenous and pathologic FICD-mediated protein AMPylation.bioRxiv : the preprint server for biology · 2024Article
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Abstract
backgroundCardiomyocytes 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.
methodsWe 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.
resultsWe 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.
conclusionsOur 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.
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