USP21-mediated deubiquitylation stimulates NuMA recruitment to the cell cortex to promote mitotic spindle orientation

IF 13.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Death and Differentiation Pub Date : 2026-06-23 DOI:10.1038/s41418-026-01786-7

Mingzheng Hu, Huixian Ma, Runa Wang, Zhenqi Yu, Jinqiong Wang, Lin Li, Difei Wang, Hanxiao Yin, Mulin Yang, Feifei Qi, Ying Shan, Huijie Zhao, Jinmin Gao, Dengwen Li, Min Liu, Jun Zhou

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Abstract

Proper orientation of the mitotic spindle is critical for a wide range of biological processes. However, the molecular mechanisms that regulate the formation of the spindle orientation machinery remain incompletely understood. In this study, we identify an essential role for ubiquitin-specific peptidase 21 (USP21)-mediated deubiquitylation in the control of spindle orientation. Histological analyses of Usp21 knockout mice revealed multiple epithelial abnormalities, including delayed corneal epithelial stratification, dilated renal tubules, and impaired skin wound healing. These defects were attributable to spindle misorientation in corresponding epithelial tissues. In vitro studies further confirmed that USP21 deficiency disrupts spindle orientation in cultured cells. Mechanistically, USP21 interacts with nuclear mitotic apparatus protein (NuMA) and removes the lysine 63-linked ubiquitylation of NuMA at lysine 1330 and lysine 1335. The deubiquitylation of NuMA triggers its interaction with Leu-Gly-Asn repeat-enriched protein (LGN), thereby recruiting NuMA to the cell cortex to form the spindle orientation machinery. Collectively, these findings uncover a previously unrecognized role for USP21 in spindle orientation and underscore its importance in epithelial development and homeostasis through the deubiquitylation of NuMA.

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usp21介导的去泛素化刺激NuMA向细胞皮层募集，促进有丝分裂纺锤体取向

有丝分裂纺锤体的正确定位对广泛的生物过程至关重要。然而，调控纺锤体取向机制形成的分子机制仍然不完全清楚。在这项研究中，我们确定了泛素特异性肽酶21 （USP21）介导的去泛素化在控制纺锤体取向中的重要作用。Usp21基因敲除小鼠的组织学分析显示多发性上皮异常，包括角膜上皮分层延迟、肾小管扩张和皮肤伤口愈合受损。这些缺陷可归因于相应上皮组织的纺锤体取向错误。体外研究进一步证实，USP21缺陷会破坏培养细胞的纺锤体取向。在机制上，USP21与核有丝分裂器蛋白（NuMA）相互作用，去除NuMA在赖氨酸1330和赖氨酸1335上赖氨酸63连接的泛素化。NuMA的去泛素化触发其与Leu-Gly-Asn重复富集蛋白（LGN）的相互作用，从而将NuMA招募到细胞皮层形成纺锤体定向机制。总的来说，这些发现揭示了USP21在纺锤体取向中一个以前未被认识到的作用，并强调了它通过NuMA的去泛素化在上皮发育和稳态中的重要性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Death and Differentiation 生物-生化与分子生物学

CiteScore

24.70

自引率

1.60%

发文量

181

审稿时长

3 months

期刊介绍： Mission, vision and values of Cell Death & Differentiation: To devote itself to scientific excellence in the field of cell biology, molecular biology, and biochemistry of cell death and disease. To provide a unified forum for scientists and clinical researchers It is committed to the rapid publication of high quality original papers relating to these subjects, together with topical, usually solicited, reviews, meeting reports, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.