Gcn5-and Bre1-mediated Set2 degradation promotes chronological aging of Saccharomyces cerevisiae
Gcn5-and Bre1-mediated Set2 degradation promotes chronological aging of Saccharomyces cerevisiae
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DOI：
10.1016/j.celrep.2023.113186
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发表时间：
2023-10-04
期刊：
影响因子：
8.8
通讯作者：
Du，Hai-Ning
中科院分区：
文献类型：
--
作者：
Li，Yu -Min;Mei，Yu -Chao;Du，Hai-Ning
转录偶联的组蛋白H3赖氨酸36三甲基化（H3 K36 me 3）的缺失导致真核生物寿命缩短。然而，老化过程中H3 K36 me 3下降的分子机制仍然知之甚少。在这里，我们报告说，甲基转移酶Set 2的降解是在芽殖酵母中按时间老化过程中H3 K36 me 3水平降低的原因。我们发现，Set 2蛋白降解过程中的细胞衰老和时序老化主要是介导的泛素结合E2酶Ubc 3和E3连接酶Bre 1。Bre 1的缺乏或泛素化的消除稳定了Set 2蛋白，维持了衰老相关基因位点的H3 K36 me 3水平，并上调了它们的基因表达，从而延长了时间寿命。我们进一步说明，Gcn 5介导的Set 2乙酰化是一个先决条件，Bre 1催化Set 2多泛素化和蛋白水解过程中老化。我们建议，两个连续的翻译后修饰调节Set 2稳态，这表明一个潜在的策略，以GCN 5-Bre 1-Set 2轴干预寿命。
Loss of transcription-coupled histone H3 lysine 36 trimethylation (H3K36me3) contributes to shorter lifespans in eukaryotes. However, the molecular mechanism of the decline of H3K36me3 during aging remains poorly understood. Here, we report that the degradation of the methyltransferase Set2 is the cause of decreased H3K36me3 levels during chronological aging in budding yeast. We show that Set2 protein degradation during cellular senescence and chronological aging is mainly mediated by the ubiquitin-conjugating E2 enzyme Ubc3 and the E3 ligase Bre1. Lack of Bre1 or abolishment of the ubiquitination stabilizes Set2 protein, sustains H3K36me3 levels at the aging-related gene loci, and upregulates their gene expression, thus leading to extended chronological lifespan. We further illustrate that Gcn5-mediated Set2 acetylation is a prerequisite for Bre1-catalyzed Set2 polyubiquitination and proteolysis during aging. We propose that two sequential post-translational modifications regulate Set2 homeostasis, suggesting a potential strategy to target the Gcn5-Bre1-Set2 axis for intervention of longevity.