FUT8-dependent core fucosylation: essential for platelet function and a target in thrombosis

BACKGROUND: FUT8 (fucosyltransferase 8) adds core fucose to the innermost N-acetylglucosamine of N-glycans on surface receptors, affecting ligand binding and downstream signaling in various cellular contexts. Here, we examine the role of FUT8-catalyzed core fucosylation in platelet activity in vivo, and we evaluate the potential antithrombotic strategy of FUT8 inhibition.

METHODS: To investigate whether the extracellular domains of platelet adhesion receptors are core fucosylated, we used genetic, biochemical, glycomics, and glycoproteomics approaches. To investigate the impact of core fucosylation on platelet receptors for their ligand affinity, platelet activation, and downstream signaling, we used binding assays, platelet aggregometry, and phospho-specific effector antibodies. To investigate the biological effect of genetic and pharmacological inhibition of FUT8, we used murine thrombosis models.

RESULTS: We identified core fucosylated N-glycans in the extracellular domains of platelet adhesion receptors, such as GPVI (glycoprotein VI) and integrin α_IIbβ₃. Core fucosylation at platelet GPVI or α_IIbβ₃ N-glycans enhanced affinity and binding to type I collagen or fibrinogen, leading to greater platelet activation and downstream signaling. In 2 murine thrombosis models, platelet-specific Fut8 deletion inhibited platelet activation and thrombus formation. Furthermore, FUT8 inhibition with FDW028 led to reduced platelet aggregation and activation, protecting mice from lethal thrombosis.

CONCLUSIONS: This study provides genetic and pharmacological evidence that FUT8-mediated core fucosylation of platelet receptors promotes platelet activation and thrombus formation. Our results suggest that FUT8 in platelets may be a therapeutic target for thrombosis-related cardiovascular diseases.