A novel role of AURKA kinase in erythroblast enucleation.

IF 8.2 1区 医学 Q1 HEMATOLOGY
Yuanlin Xu, Peijun Jia, Yating Li, Huan Zhang, Jingxin Zhang, Wanxin Li, Yazhe Zhen, Yan Li, Jiaming Cao, Tingting Zheng, Yihan Wang, Yanyan Liu, Xiuli An, Shijie Zhang
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Abstract

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.

AURKA 激酶在红细胞去核过程中的新作用
哺乳动物红细胞的生成需要在红细胞末期分化的后期将极化的细胞核驱逐出去。然而,人们对球形红细胞决定核极化方向并在核排出过程中保持不对称的机制知之甚少。考虑到红细胞去核类似于不对称细胞分裂,以及极光激酶在有丝分裂中的关键作用,我们试图研究极光激酶在红细胞去核中的功能。我们发现,AURKA(极光激酶 A)在正色红细胞中大量表达。耐人寻味的是,高分辨率共聚焦显微镜分析表明,AURKA在极化过程中与中心体共同定位在细胞核与其膜接触点相反的一侧,随后在出核时转位到突出核的前端。从机理上讲,AURKA通过与i-微管蛋白相互作用来调控中心体的成熟和定位,为细胞核提供极化定向。此外,我们还发现鸟嘌呤核苷酸交换因子ECT2(上皮细胞转化2)是AURKA新的相互作用蛋白和泛素化底物。在形成核突起后,AURKA转位到突起核的前端直接降解ECT2,这在一定程度上依赖于AURKA的激酶活性。此外,ECT2的敲除能挽救因AURKA抑制而受损的突核。我们的研究结果揭示了极光激酶在建立核极化和最终核挤出过程中的作用,这一作用以前未被认识,并为红细胞去核提供了新的机理认识。
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来源期刊
Haematologica
Haematologica 医学-血液学
CiteScore
14.10
自引率
2.00%
发文量
349
审稿时长
3-6 weeks
期刊介绍: Haematologica is a journal that publishes articles within the broad field of hematology. It reports on novel findings in basic, clinical, and translational research. Scope: The scope of the journal includes reporting novel research results that: Have a significant impact on understanding normal hematology or the development of hematological diseases. Are likely to bring important changes to the diagnosis or treatment of hematological diseases.
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