Li Xuehui, Mei Yang, Yan Bowen, Vitriol Eric, Huang Suming, Ji Peng, Qiu Yi
Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL, USA.
Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Haematologica. 2017 Jun;102(6):984-994. doi: 10.3324/haematol.2016.161513. Epub 2017 Mar 2.
The formin protein mDia2 plays a critical role in a number of cellular processes through its ability to promote nucleation and elongation of actin filaments. In erythroblasts, this includes control of cytokinesis and enucleation by regulating contractile actin ring formation. Here we report a novel mechanism of how mDia2 is regulated: through acetylation and deacetylation at lysine 970 in the formin homology 2 domain. Ectopic expression of an acetyl-mimic mDia2 mutant in mouse erythroblasts is sufficient to abolish contractile actin ring formation at the cleavage furrow and subsequent erythrocyte cytokinesis and enucleation. We also identified that class II histone deacetylase 6 deacetylates and subsequently activates mDia2. Knockdown or inhibition of histone deacetylase 6 impairs contractile actin ring formation, and expression of a non-acetyl-mimic mDia2 mutant restores the contractile actin ring and rescues the impairment of enucleation. In addition to revealing a new step in mDia2 regulation, this study may unveil a novel regulatory mechanism of formin-mediated actin assembly, since the K970 acetylation site is conserved among Dia proteins.
formin蛋白mDia2通过其促进肌动蛋白丝成核和延伸的能力，在许多细胞过程中发挥关键作用。在成红细胞中，这包括通过调节收缩性肌动蛋白环的形成来控制胞质分裂和去核。在此，我们报告一种关于mDia2如何被调控的新机制：通过在formin同源2结构域的赖氨酸970处进行乙酰化和去乙酰化。在小鼠成红细胞中异位表达乙酰模拟mDia2突变体足以消除分裂沟处收缩性肌动蛋白环的形成以及随后的红细胞胞质分裂和去核。我们还确定II类组蛋白去乙酰化酶6使mDia2去乙酰化并随后激活mDia2。敲低或抑制组蛋白去乙酰化酶6会损害收缩性肌动蛋白环的形成，而非乙酰模拟mDia2突变体的表达可恢复收缩性肌动蛋白环并挽救去核障碍。除了揭示mDia2调控的一个新步骤外，这项研究可能还揭示了formin介导的肌动蛋白组装的一种新型调控机制，因为K970乙酰化位点在Dia蛋白中是保守的。
