IRAP Drives Ribosomal Degradation to Refuel Energy for Platelet Activation during Septic Thrombosis

Area of Science:

• Biochemistry
• Cell Biology
• Hematology

Background:

• Platelets are crucial in pathophysiological processes, requiring significant energy for activation.
• The source of abundant energy in platelets has been a long-standing question.
• Septic thrombosis involves platelet hyperactivation and energy metabolism.

Purpose of the Study:

• To investigate the role of insulin-regulated aminopeptidase (IRAP) in platelet energy metabolism and activation.
• To elucidate the mechanism by which IRAP regulates energy supply in activated platelets.
• To evaluate IRAP as a therapeutic target for septic thrombosis.

Main Methods:

• Investigated IRAP's function in activated platelets.
• Examined IRAP's interaction with endosome membrane proteins.
• Analyzed IRAP-mediated ribophagy, amino acid recycling, and metabolic reprogramming.
• Assessed the impact of IRAP inhibition on platelet activation and septic thrombosis models.

Main Results:

• IRAP promotes energy regeneration in activated platelets.
• IRAP facilitates granule release and lysosomal degradation of ribosomes (ribophagy) in an mTORC1- and S-acylation-dependent manner.
• IRAP-mediated amino acid recycling fuels aerobic glycolysis, reprogramming energy metabolism for prolonged platelet activation.
• Targeted IRAP blockade significantly reduces platelet hyperactivation and alleviates septic thrombosis.

Conclusions:

• IRAP is a key regulator of energy metabolism in activated platelets.
• IRAP-mediated ribophagy and subsequent metabolic reprogramming provide essential energy for platelet function and survival.
• Inhibiting IRAP offers a promising therapeutic strategy to manage platelet hyperactivation and septic thrombosis.