RNA translational regulation by CPEB4 orchestrates platelet function and pathophysiology

Platelets are highly specialized anucleate cells that play crucial roles in haemostasis, inflammation and disease. Recent data suggest that mRNA translational control is the primary mechanism of gene regulation in platelets. This study unveils a novel pathway to control mRNA translation and protein expression in platelets via the mRNA binding protein CPEB4. We found high CPEB4 expression levels in human and mouse platelets, colocalizing with cytoskeletal proteins. In vivo loss-of-function studies, using the megakaryocytic lineage-specific Pf4-Cre transgenic mice crossed with a strain containing loxP-flanked CPEB4 (Pf4+:Cpeb4–/– mice), revealed a significant reduction of platelet activation and aggregation. These effects were specific to mature platelets, as CPEB4 deficiency did not significantly impact megakaryocytopoiesis. Functional assays, including tail bleeding and collagen-induced embolism, demonstrated impaired coagulation in Pf4+:Cpeb4–/– mice compared to controls. Furthermore, proteomics analysis of resting and activated platelets from Pf4–:Cpeb4+/+ and Pf4+:Cpeb4–/– mice identified a molecular signature of proteins and networks regulated by CPEB4, including those involved in haemostasis and platelet clearance. Our study reveals CPEB4-mediated mRNA translational regulation as a novel fine-tuning mechanism for modulating protein synthesis in platelets, with significant functional consequences in both physiological and pathological conditions.