A phosphorylation switch in the Mediator MED15 controls cellular senescence and cognitive decline.

IF 12.5 1区生物学 Q1 CELL BIOLOGY

Cell Discovery Pub Date : 2025-08-19 DOI:10.1038/s41421-025-00820-1

Haozheng Li, Yuanming Zheng, Chunlei Yuan, Jiayi Wang, Xiaying Zhao, Ming Yang, Defei Xiong, Yenan Yang, Yunpeng Dai, Yiming Gao, Yuqi Wang, Lei Xue, Gang Wang

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引用次数: 0

Abstract

A hallmark of aging is chronic systemic inflammation, which is exacerbated by the hypersecretory aging phenotype known as the senescence-associated secretory phenotype (SASP). How the SASP is initiated to accelerate tissue inflammation and aging is an outstanding question in aging biology. Here, we showed that phosphorylation of the Mediator subunit MED15 at T603 is able to control the SASP and aging. Transforming growth factor-β selectively induces CDK1-mediated MED15 T603 phosphorylation to control SASP gene expression. The MED15 T603 dephosphorylated mutant (T603A) inhibits the SASP and cell senescence, whereas the T603 phosphorylation-mimicking mutant (T603D) has the opposite effect. Mechanistically, forkhead box protein A1 preferentially binds to unphosphorylated but not phosphorylated MED15 at T603 to suppress SASP gene expression. Notably, aging mice harboring dephosphorylated mutation in this phosphosite exhibit improved learning and memory through the attenuation of the SASP across tissues. Overall, our study indicates that MED15 T603 phosphorylation serves as a control switch for SASP production, which underlies tissue aging and cognitive decline and provides a novel target for age-related pathogenesis.

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介质MED15中的磷酸化开关控制细胞衰老和认知能力下降。

衰老的一个标志是慢性全身性炎症，这种炎症会因称为衰老相关分泌型（SASP）的高分泌性衰老表型而加剧。SASP如何启动加速组织炎症和衰老是衰老生物学中的一个突出问题。在这里，我们发现调解亚基MED15在T603的磷酸化能够控制SASP和衰老。转化生长因子-β选择性诱导cdk1介导的MED15 T603磷酸化调控SASP基因表达。MED15 T603去磷酸化突变体（T603A）抑制SASP和细胞衰老，而T603磷酸化模拟突变体（T603D）具有相反的作用。机制上，叉头盒蛋白A1优先结合T603处未磷酸化但未磷酸化的MED15，抑制SASP基因表达。值得注意的是，携带该磷酸体去磷酸化突变的衰老小鼠通过组织间SASP的衰减表现出学习和记忆的改善。总的来说，我们的研究表明MED15 T603磷酸化是SASP产生的控制开关，SASP是组织衰老和认知能力下降的基础，并为年龄相关的发病机制提供了一个新的靶点。

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 Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology

CiteScore

24.20

自引率

0.60%

发文量

120

审稿时长

20 weeks

期刊介绍： Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.