14-3-3ε inhibits premature centriole disengagement by inhibiting the activity of Plk1 and separase.

IF 3.3 3区 生物学 Q3 CELL BIOLOGY
Journal of cell science Pub Date : 2025-07-15 Epub Date: 2025-07-18 DOI:10.1242/jcs.263808
Monika A Jaiswal, Akshay Karn, Aparna Das, Anisha Kumari, Shilu Tiwari, Sorab N Dalal
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引用次数: 0

Abstract

The 14-3-3 protein family regulates several pathways in mammalian cells, including centrosome duplication. However, the precise mechanisms by which 14-3-3 paralogs regulate the centrosome cycle remain unclear. To identify the mechanisms by which 14-3-3ε regulates centrosome duplication, we altered two conserved acidic residues in the 14-3-3ε phospho-peptide-binding pocket that regulate complex formation and dissociation with the associated ligands, D127 and E134, to alanine. Altering these residues to alanine led to opposing effects on centrosome duplication; the D127A mutant inhibited centrosome duplication, whereas cells expressing the E134A mutant showed the presence of supernumerary centrosomes. We demonstrate that 14-3-3ε does not inhibit centriole duplication, as reported for 14-3-3γ, but inhibits centriole disengagement. Using a combination of pharmacological and genetic approaches, we demonstrate that 14-3-3ε inhibits the activity of Plk1 and separase [also known as separin (ESPL1)], leading to disengagement defects that ultimately lead to decreased proliferation and cell death. Our work demonstrates that different 14-3-3 paralogs regulate different steps in the centrosome cycle and that disrupting complex formation between 14-3-3ε and Plk1 or separase could be a novel therapeutic strategy in tumor cells.

14-3-3通过抑制Plk1和分离酶活性抑制中心粒过早脱离。
14-3-3蛋白家族调节哺乳动物细胞中的几种途径,包括中心体复制。然而,14-3-3相似体调控中心体周期的确切机制尚不清楚。为了确定14-3-3 α调节中心体复制的机制,我们将14-3-3 α磷酸化肽结合口袋中的两个保守的酸性残基改变为丙氨酸,这些残基调节复合物的形成和与相关配体D127和E134的解离。将这些残基转化为丙氨酸会对中心体复制产生相反的影响;D127A突变体抑制中心体复制,而表达E134A突变体的细胞显示存在多余的中心体。我们证明14-3-3γ并不抑制中心粒重复,但抑制中心粒脱离。利用药理学和遗传学方法的结合,我们证明14-3-3 /抑制Plk1和分离酶的活性,导致脱离缺陷,最终导致增殖减少和细胞死亡。我们的研究表明,不同的14-3-3类似物调节着中心体周期的不同步骤,破坏14-3-3和Plk1或分离酶之间的复合物形成可能是肿瘤细胞的一种新的治疗策略。
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
Journal of cell science
Journal of cell science 生物-细胞生物学
CiteScore
7.30
自引率
2.50%
发文量
393
审稿时长
1.4 months
期刊介绍: Journal of Cell Science publishes cutting-edge science, encompassing all aspects of cell biology.
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