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Twinfilin 2a regulates platelet reactivity and turnover in mice
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Univ Hosp, Inst Expt Biomed 1, Josef Schneider Str 2, D-97080 Wurzburg, Germany.;Univ Wurzburg, Rudolf Virchow Ctr, Josef Schneider Str 2, D-97080 Wurzburg, Germany..
Univ Hosp, Inst Expt Biomed 1, Josef Schneider Str 2, D-97080 Wurzburg, Germany.;Univ Wurzburg, Rudolf Virchow Ctr, Josef Schneider Str 2, D-97080 Wurzburg, Germany..
Univ Hosp, Inst Expt Biomed 1, Josef Schneider Str 2, D-97080 Wurzburg, Germany.;Univ Wurzburg, Rudolf Virchow Ctr, Josef Schneider Str 2, D-97080 Wurzburg, Germany..
Univ Hosp, Inst Expt Biomed 1, Josef Schneider Str 2, D-97080 Wurzburg, Germany.;Univ Wurzburg, Rudolf Virchow Ctr, Josef Schneider Str 2, D-97080 Wurzburg, Germany.;Univ Birmingham, Inst Cardiovasc Sci, Coll Med & Dent Sci, Birmingham, W Midlands, England..
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2017 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 130, no 15, 1746-1756 p.Article in journal (Refereed) Published
Abstract [en]

Regulated reorganization of the actin cytoskeleton is a prerequisite for proper platelet production and function. Consequently, defects in proteins controlling actin dynamics have been associated with platelet disorders in humans andmice. Twinfilin 2a (Twf2a) is a small actin-binding protein that inhibits actin filament assembly by sequestering actin monomers and capping filament barbed ends. Moreover, Twf2a binds heterodimeric capping proteins, but the role of this interaction in cytoskeletal dynamics has remained elusive. Even though Twf2a has pronounced effects on actin dynamics in vitro, only little is known about its function in vivo. Here, we report that constitutive Twf2a-deficient mice (Twf2a(-/-)) display mild macrothrombocytopenia due to a markedly accelerated platelet clearance in the spleen. Twf2a(-/-) platelets showed enhanced integrin activation and a-granule release in response to stimulation of (hem) immunoreceptor tyrosine-based activationmotif (ITAM) and G-protein-coupled receptors, increased adhesion and aggregate formation on collagen I under flow, and accelerated clot retraction and spreading on fibrinogen. In vivo, Twf2a deficiency resulted in shortened tail bleeding times and faster occlusive arterial thrombus formation. The hyperreactivity of Twf2a(-/-) platelets was attributed to enhanced actin dynamics, characterized by an increased activity of n-cofilin and profilin 1, leading to a thickened cortical cytoskeleton and hence sustained integrin activation by limiting calpain- mediated integrin inactivation. In summary, our results reveal the first in vivo functions of mammalian Twf2a and demonstrate that Twf2a-controlled actin rearrangements dampen platelet activation responses in a n-cofilin- and profilin 1-dependent manner, thereby indirectly regulating platelet reactivity and half-life in mice.

Place, publisher, year, edition, pages
AMER SOC HEMATOLOGY , 2017. Vol. 130, no 15, 1746-1756 p.
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Hematology
Identifiers
URN: urn:nbn:se:uu:diva-337333DOI: 10.1182/blood-2017-02-770768ISI: 000412820200012PubMedID: 28743718OAI: oai:DiVA.org:uu-337333DiVA: diva2:1169018
Available from: 2017-12-22 Created: 2017-12-22 Last updated: 2017-12-22Bibliographically approved

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