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Coactosin-like 1 integrates signaling critical for shear-dependent thrombus formation in mouse platelets

Platelet aggregate formation is a multistep process involving receptor-mediated, as well as biomechanical, signaling cascades, which are highly dependent on actin dynamics. We have previously shown that actin depolymerizing factor (ADF)/n-cofilin and Twinfilin 2a, members of the ADF homology (ADF-H)...

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Autores principales: Scheller, Inga, Stritt, Simon, Beck, Sarah, Peng, Bing, Pleines, Irina, Heinze, Katrin G., Braun, Attila, Otto, Oliver, Ahrends, Robert, Sickmann, Albert, Bender, Markus, Nieswandt, Bernhard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ferrata Storti Foundation 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271572/
https://www.ncbi.nlm.nih.gov/pubmed/31582545
http://dx.doi.org/10.3324/haematol.2019.225516
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author Scheller, Inga
Stritt, Simon
Beck, Sarah
Peng, Bing
Pleines, Irina
Heinze, Katrin G.
Braun, Attila
Otto, Oliver
Ahrends, Robert
Sickmann, Albert
Bender, Markus
Nieswandt, Bernhard
author_facet Scheller, Inga
Stritt, Simon
Beck, Sarah
Peng, Bing
Pleines, Irina
Heinze, Katrin G.
Braun, Attila
Otto, Oliver
Ahrends, Robert
Sickmann, Albert
Bender, Markus
Nieswandt, Bernhard
author_sort Scheller, Inga
collection PubMed
description Platelet aggregate formation is a multistep process involving receptor-mediated, as well as biomechanical, signaling cascades, which are highly dependent on actin dynamics. We have previously shown that actin depolymerizing factor (ADF)/n-cofilin and Twinfilin 2a, members of the ADF homology (ADF-H) protein family, have distinct roles in platelet formation and function. Coactosin-like 1 (Cotl1) is another ADF-H protein that binds actin and was also shown to enhance biosynthesis of pro-inflammatory leukotrienes (LT) in granulocytes. Here, we generated mice lacking Cotl1 in the megakaryocyte lineage (Cotl1(−/−)()) to investigate its role in platelet production and function. Absence of Cotl1 had no impact on platelet counts, platelet activation or cytoskeletal reorganization under static conditions in vitro. In contrast, Cotl1 deficiency markedly affected platelet aggregate formation on collagen and adhesion to immobilized von Willebrand factor at high shear rates in vitro, pointing to an impaired function of the platelet mechanoreceptor glycoprotein (GP) Ib. Furthermore, Cotl1(−/−)platelets exhibited increased deformability at high shear rates, indicating that the GPIb defect may be linked to altered biomechanical properties of the deficient cells. In addition, we found that Cotl1 deficiency markedly affected platelet LT biosynthesis. Strikingly, exogenous LT addition restored defective aggregate formation of Cotl1(−/−) platelets at high shear in vitro, indicating a critical role of platelet-derived LT in thrombus formation. In vivo, Cotl1 deficiency translated into prolonged tail bleeding times and protection from occlusive arterial thrombus formation. Together, our results show that Cotl1 in platelets is an integrator of biomechanical and LT signaling in hemostasis and thrombosis.
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spelling pubmed-72715722020-06-12 Coactosin-like 1 integrates signaling critical for shear-dependent thrombus formation in mouse platelets Scheller, Inga Stritt, Simon Beck, Sarah Peng, Bing Pleines, Irina Heinze, Katrin G. Braun, Attila Otto, Oliver Ahrends, Robert Sickmann, Albert Bender, Markus Nieswandt, Bernhard Haematologica Articles Platelet aggregate formation is a multistep process involving receptor-mediated, as well as biomechanical, signaling cascades, which are highly dependent on actin dynamics. We have previously shown that actin depolymerizing factor (ADF)/n-cofilin and Twinfilin 2a, members of the ADF homology (ADF-H) protein family, have distinct roles in platelet formation and function. Coactosin-like 1 (Cotl1) is another ADF-H protein that binds actin and was also shown to enhance biosynthesis of pro-inflammatory leukotrienes (LT) in granulocytes. Here, we generated mice lacking Cotl1 in the megakaryocyte lineage (Cotl1(−/−)()) to investigate its role in platelet production and function. Absence of Cotl1 had no impact on platelet counts, platelet activation or cytoskeletal reorganization under static conditions in vitro. In contrast, Cotl1 deficiency markedly affected platelet aggregate formation on collagen and adhesion to immobilized von Willebrand factor at high shear rates in vitro, pointing to an impaired function of the platelet mechanoreceptor glycoprotein (GP) Ib. Furthermore, Cotl1(−/−)platelets exhibited increased deformability at high shear rates, indicating that the GPIb defect may be linked to altered biomechanical properties of the deficient cells. In addition, we found that Cotl1 deficiency markedly affected platelet LT biosynthesis. Strikingly, exogenous LT addition restored defective aggregate formation of Cotl1(−/−) platelets at high shear in vitro, indicating a critical role of platelet-derived LT in thrombus formation. In vivo, Cotl1 deficiency translated into prolonged tail bleeding times and protection from occlusive arterial thrombus formation. Together, our results show that Cotl1 in platelets is an integrator of biomechanical and LT signaling in hemostasis and thrombosis. Ferrata Storti Foundation 2020-06 /pmc/articles/PMC7271572/ /pubmed/31582545 http://dx.doi.org/10.3324/haematol.2019.225516 Text en Copyright© 2020 Ferrata Storti Foundation Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher.
spellingShingle Articles
Scheller, Inga
Stritt, Simon
Beck, Sarah
Peng, Bing
Pleines, Irina
Heinze, Katrin G.
Braun, Attila
Otto, Oliver
Ahrends, Robert
Sickmann, Albert
Bender, Markus
Nieswandt, Bernhard
Coactosin-like 1 integrates signaling critical for shear-dependent thrombus formation in mouse platelets
title Coactosin-like 1 integrates signaling critical for shear-dependent thrombus formation in mouse platelets
title_full Coactosin-like 1 integrates signaling critical for shear-dependent thrombus formation in mouse platelets
title_fullStr Coactosin-like 1 integrates signaling critical for shear-dependent thrombus formation in mouse platelets
title_full_unstemmed Coactosin-like 1 integrates signaling critical for shear-dependent thrombus formation in mouse platelets
title_short Coactosin-like 1 integrates signaling critical for shear-dependent thrombus formation in mouse platelets
title_sort coactosin-like 1 integrates signaling critical for shear-dependent thrombus formation in mouse platelets
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271572/
https://www.ncbi.nlm.nih.gov/pubmed/31582545
http://dx.doi.org/10.3324/haematol.2019.225516
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