Advertisement

Twinfilin 2a regulates platelet reactivity and turnover in mice

Simon Stritt, Sarah Beck, Isabelle C. Becker, Timo Vögtle, Markku Hakala, Katrin G. Heinze, Xiaoping Du, Markus Bender, Attila Braun, Pekka Lappalainen and Bernhard Nieswandt

Key Points

  • Deficiency in twinfilin 2a causes macrothrombocytopenia and hyperreactivity of platelets in mice.

  • We provide the first in vivo evidence for an inhibitory function of twinfilin 2a in platelet actin dynamics.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

Abstract

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 and mice. 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 α-granule release in response to stimulation of (hem) immunoreceptor tyrosine-based activation motif (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.

  • Submitted February 27, 2017.
  • Accepted July 21, 2017.
View Full Text