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Deduced Roles of Cardiac 14‐3‐3 Protein Interactome in Heart Metabolism, Protein Synthesis and Proteostasis

The 14‐3‐3 protein family is known to interact with many proteins in non‐cardiac cell types to regulate multiple signaling pathways, particularly those relating to energy and protein homeostasis, and the 14‐3‐3 network is a therapeutic target of critical metabolic and proteostatic signalings in cancer and neurological diseases. Although the heart is critically sensitive to nutrient and energy alterations, and multiple signaling pathways coordinate to maintain the cardiac cell homeostasis, neither the structure of cardiac 14‐3‐3 protein interactome nor potential functional roles of 14‐3‐3 protein‐protein interactions (PPIs) has been explored in heart. Here, we evaluated both RNA expression and protein abundance of 14‐3‐3 isoforms in mouse left ventricle, followed by co‐immunoprecipitation of 14‐3‐3 proteins and mass spectrometry in left ventricle. We identified 594 proteins comprising the cardiac 14‐3‐3 interactome. Immunofluorescence assays indicated that 14‐3‐3 proteins localize in mitochondria and ribosome. Multiple bioinformatic analyses indicated that more than half of proteins bound to 14‐3‐3 are related to mitochondria, and the deduced functions of the mitochondrial 14‐3‐3 network are to regulate cardiac ATP production via interactions with mitochondrial inner membrane proteins, especially those in mitochondrial complex I and V, and to regulate cardiac fatty acid metabolism via interactions with enzymes within mitochondrial matrix. 14‐3‐3 protein binding to ribosomal proteins may triage energy production to coordinate protein synthesis and protein quality control. In summary, we establish the comprehensive landscape of cardiac 14‐3‐3 PPIs, dissecting its structure, deducing its function to have a major role to regulate cardiac metabolic homeostasis and proteostasis. Because 14‐3‐3 binds to proteins that are crucial to cardiac functions and heart health, the cardiac 14‐3‐3 interactome may be a potential therapeutic target in cardiovascular metabolic and proteostatic disease states, as it already is in cancer therapy.