Impaired Platelet Function in Sept8-Deficient Mice In Vitro

Katharina Neubauer; Kerstin Jurk; Victoria Petermann; Elena Kumm; Barbara Zieger

doi:10.1055/s-0040-1718733

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2021; 121(04): 484-494
DOI: 10.1055/s-0040-1718733

Cellular Haemostasis and Platelets

Impaired Platelet Function in Sept8-Deficient Mice In Vitro

Katharina Neubauer^*

¹Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

,

Kerstin Jurk‡^*

²Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany

,

Victoria Petermann

²Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany

,

Elena Kumm

²Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany

,

Barbara Zieger

¹Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

› Author Affiliations

Abstract

Septins (Septs) are a widely expressed protein family of 13 mammalian members, recognized as a unique component of the cytoskeleton. In human platelets, we previously described that SEPT4 and SEPT8 are localized surrounding α-granules and move to the platelet surface after activation, indicating a possible role in platelet physiology. In this study, we investigated the impact of Sept8 on platelet function in vitro using Sept8-deficient mouse platelets. Deletion of Sept8 in mouse platelets caused a pronounced defect in activation of the fibrinogen receptor integrin α_IIbβ_3, α-granule exocytosis, and aggregation, especially in response to the glycoprotein VI agonist convulxin. In contrast, δ-granule and lysosome exocytosis of Sept8-deficient platelets was comparable to wild-type platelets. Sept8-deficient platelet binding to immobilized fibrinogen under static conditions was diminished and spreading delayed. The procoagulant activity of Sept8-deficient platelets was reduced in response to convulxin as determined by lactadherin binding. Also thrombin generation was decreased relative to controls. Thus, Sept8 is required for efficient integrin α_IIbβ₃ activation, α-granule release, platelet aggregation, and contributes to platelet-dependent thrombin generation. These results revealed Sept8 as a modulator of distinct platelet functions involved in primary and secondary hemostatic processes.

Keywords

platelets - septins - exocytosis - glycoprotein VI - coagulation

Full Text

References

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Supplementary Material

Supplementary Material