School of Life Sciences, Zhengzhou University, Zhengzhou, China; Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou.
School of Life Sciences, Zhengzhou University, Zhengzhou.
Haematologica. 2024 Nov 1;109(11):3721-3734. doi: 10.3324/haematol.2023.284873.
Generation of mammalian red blood cells requires the expulsion of polarized nuclei late in terminal erythroid differentiation. However, the mechanisms by which spherical erythroblasts determine the direction of nuclear polarization and maintain asymmetry during nuclear expulsion are poorly understood. Given the analogy of erythroblast enucleation to asymmetric cell division and the key role of Aurora kinases in mitosis, we sought to investigate the function of Aurora kinases in erythroblast enucleation. We found that AURKA (Aurora kinase A) is abundantly expressed in orthochromatic erythroblasts. Intriguingly, high-resolution confocal microscopy analyses revealed that AURKA co-localized with the centrosome on the side of the nucleus opposite its membrane contact point during polarization and subsequently translocated to the anterior end of the protrusive nucleus upon nuclear exit. Mechanistically, AURKA regulated centrosome maturation and localization via interaction with γ-tubulin to provide polarization orientation for the nucleus. Furthermore, we identified ECT2 (epithelial cell transforming 2), a guanine nucleotide exchange factor, as a new interacting protein and ubiquitination substrate of AURKA. After forming the nuclear protrusion, AURKA translocated to the anterior end of the protrusive nucleus to directly degrade ECT2, which is partly dependent on kinase activity of AURKA. Moreover, knockdown of ECT2 rescued impaired enucleation caused by AURKA inhibition. Our findings have uncovered a previously unrecognized role of Aurora kinases in the establishment of nuclear polarization and eventual nuclear extrusion and provide new mechanistic insights into erythroblast enucleation.
哺乳动物红细胞的生成需要在终末红细胞分化后期排出极化核。然而，球形红细胞确定核极化方向并在核排出过程中维持不对称性的机制尚不清楚。鉴于红细胞去核类似于不对称细胞分裂，以及 Aurora 激酶在有丝分裂中的关键作用，我们试图研究 Aurora 激酶在红细胞去核中的功能。我们发现 AURKA（Aurora 激酶 A）在正染色质红细胞中大量表达。有趣的是，高分辨率共聚焦显微镜分析显示，AURKA 在极化过程中与中心体在细胞核的膜接触点相对的一侧共定位，随后在核排出时迁移到突起核的前端。在机制上，AURKA 通过与 γ-微管蛋白相互作用来调节中心体成熟和定位，为核提供极化方向。此外，我们鉴定了 ECT2（上皮细胞转化 2），一种鸟嘌呤核苷酸交换因子，作为 AURKA 的新相互作用蛋白和泛素化底物。形成核突起后，AURKA 迁移到突起核的前端，直接降解 ECT2，这部分依赖于 AURKA 的激酶活性。此外，ECT2 的敲低挽救了 AURKA 抑制引起的去核受损。我们的发现揭示了 Aurora 激酶在核极化的建立以及最终核排出中的先前未被认识的作用，并为红细胞去核提供了新的机制见解。
