Targeting the MNK1-MYH9 Axis Blocks YAP1 Recruitment to Prevent Thrombosis and Platelet Activation-Induced NETosis

Area of Science:

• Immunology
• Hematology
• Molecular Biology

Background:

• Platelet activation and neutrophil extracellular trap (NET) formation are key to immunothrombosis.
• The molecular mechanisms linking these processes are not fully understood.

Purpose of the Study:

• To elucidate the role of Yes-associated protein 1 (YAP1) and non-muscle myosin heavy chain 9 (MYH9) in platelet activation.
• To identify novel therapeutic targets for immunothrombosis.

Main Methods:

• Investigated protein-protein interactions using biochemical assays.
• Developed and tested peptide (R13) and small molecule (MD2) inhibitors.
• Assessed the impact of inhibitors on platelet activation and NET formation.

Main Results:

• YAP1 binds MYH9 to promote platelet activation and thrombosis.
• MAPK-interacting kinase 1 (MNK1) competitively inhibits YAP1-MYH9 binding.
• MD2 stabilizes the MNK1-MYH9 complex, blocking YAP1 recruitment and suppressing platelet activation and NET formation.
• Inhibition is hemostatically safe.

Conclusions:

• A novel YAP1-MYH9 signaling axis regulates platelet activation.
• Targeting the MNK1-MYH9 interaction offers a promising therapeutic strategy for immunothrombosis.
• This approach provides hemostatically sparing inhibition of platelet activation and NET formation.