Skip to main content
ISTH 2024 Main banner
Back
CME Evaluation

Oral Communication Session

Platelets and Megakaryocytes

Session: Mega-insights

OC 18.5 - G6PD controls thrombopoiesis by monitoring TMOD3-regulated actin reorganization

Sunday, June 23, 2024
10:30 – 10:45 ICT
Room: 211 A-D

    Presenting Author(s)

  • Min Xin, PhD

    Student, Dr.
    Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
    shanghai, Shanghai, China (People's Republic)

    • Co-Author(s)

  • Chihao Zhang

    Student
    Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
    shanghai, Shanghai, China (People's Republic)

  • XF

    Xuemei Fan

    Professor; engaged in the study of the mechanism of hemorrhage and thrombosis
    Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
    shanghai, Shanghai, China (People's Republic)

  • YX

    Yanyan Xu

    Professor; engaged in the study of the mechanism of hemorrhage and thrombosis
    Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
    shanghai, Shanghai, China (People's Republic)

  • JD

    Jing Dai

    Professor; engaged in the study of the mechanism of hemorrhage and thrombosis
    Department of Clinical Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
    Shanghai, Shanghai, China (People's Republic)

Background: Megakaryocytes (MKs), which undergo a complex series of biological processes, including endomitosis, cytoplasmic maturation, and pro-platelets formation (PPF), are responsible for the production of platelets. Glucose metabolism has been proved to be essential for thrombopoiesis and is composed of glycolysis, tricarboxylic acid cycle and pentose phosphate pathway (PPP), which are interconnected and mutually influential. PPP is the only pathway that cannot produce ATP. As the first step and rate-limiting catalytic enzyme of PPP, glucose-6-phosphate dehydrogenase (G6PD) is vital for the proliferation and differentiation of many kinds of cells, however, its effect on platelet production has not been explored.

Aims: To investigate the role and underlying mechanism of G6PD in platelet biogenesis.

Methods: The maturation and differentiation of MKs were evaluated by flow cytometry, immunofluorescence and confocal microscopy. Seahorse assay, glucose metabolic flux and metabolomics were used to determine the level of metabolism. Immunoprecipitation, mass spectrometry and WB were used to explore the further molecular mechanism.

Results: We found that patients with severe G6PD deficiency had higher platelet counts. A similar phenotype existed in G6pd-/- mice and G6pd-/- MKs exhibited enhanced PPF. No significant differences in the metabolism of substance and energy in platelets were shown. We then found that G6PD was able to interact with tropomodulin-3 (TMOD3), a negative regulatory protein of actin cytoskeleton reorganization. This interaction was shown to be in a NADP+-dependent manner and enhance the binding of TMOD3 to ACTIN. Addition of NADP+ to MKs increased the colocalization of TMOD3 and ACTIN that hinders the assembly of actin filament, which further confined the process of pro-platelets formation.

Conclusion(s): Our study reveals that G6PD confines pro-platelets formation of megakaryocytes by interacting with TMOD3 in a NADP+-dependent manner to negatively regulate the reorganization of the actin cytoskeleton.