湖南师范大学生命科学学院翟宗昭团队取得一项新突破。他们研制了Lsp2将mTORC1与果蝇的TOP mRNA翻译和寿命联系起来。相关论文发表在2026年9月23日出版的《自然》杂志上。

雷帕霉素机制性靶标复合物1（mTORC1）感知营养可用性，以协调对生理稳态和衰老至关重要的代谢过程。mTORC1通过4E-BP翻译抑制因子优先调控含5′末端寡嘧啶（TOP）基序的mRNA（主要编码核糖体蛋白）的翻译；然而，mTORC1的这一功能对雷帕霉素抑制具有抗性。TOP mRNA异常丰富，因此对细胞造成主要的翻译负担，但其翻译如何在生理上被调节并与寿命相关联仍不清楚。在此，研究人员表明，Lsp2——此前已知是一种储存蛋白——也是一种脂肪效应物和mTORC1的反馈激活因子，调控果蝇的寿命。Lsp2的表达由必需氨基酸通过mTORC1诱导，并受营养充足性额外信号的门控。Lsp2的基因敲除可显著延长寿命，而不损害繁殖等关键生活史特征。翻译组学分析显示，Lsp2缺失以4E-BP依赖的方式选择性降低整体TOP mRNA翻译，从而通过一种不同于雷帕霉素效应的机制延长寿命。在演化上，TOP基序与4E-BP共同出现，并存在于几乎所有果蝇核糖体蛋白mRNA中。此外，研究人员表明，TOP基序在翻译控制中的作用延伸至果蝇。总之，研究人员的发现揭示了一种营养诱导的生理因子，它放大mTORC1在TOP mRNA翻译中的输出并调控机体寿命。

附：英文原文

Title: Lsp2 links mTORC1 to TOP mRNA translation and lifespan in Drosophila

Author: Wang, Jun, Cai, Zixin, Gu, Jiaojiao, Xiong, Shiqi, Yi, Jianhan, Yang, Meng, Chang, Kexin, Ning, Xinrui, Wen, Yilin, Yan, Yan, Lu, Jiongming, Wang, Yirong, Zhai, Zongzhao

Issue&Volume: 2026-09-23

Abstract: Mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability to orchestrate metabolic processes that are crucial for physiological homeostasis and ageing1. mTORC1 preferentially regulates the translation of 5′-terminal oligopyrimidine (TOP) motif-containing mRNAs (which encode mainly ribosomal proteins) through the 4E-BP translational repressor2; however, this function of mTORC1 is resistant to rapamycin inhibition3. TOP mRNAs are exceptionally abundant, and thus impose a major translational burden on cells, but how their translation is physiologically tuned and linked with lifespan remains unclear. Here we show that Lsp2, which was previously known to be a storage protein4, is also an adipose effector and feedback activator of mTORC1 that modulates lifespan in Drosophila. Expression of Lsp2 is induced by essential amino acids through mTORC1 and is gated by additional signals of nutrient sufficiency. Genetic ablation of Lsp2 robustly extends lifespan without impairing key life history traits such as reproduction. Translatomic profiling shows that loss of Lsp2 selectively reduces global TOP mRNA translation in a 4E-BP-dependent manner, thereby extending lifespan through a mechanism distinct from the effects of rapamycin. Evolutionarily, TOP motifs co-emerged with 4E-BP and are present in nearly all Drosophila ribosomal protein mRNAs. Moreover, we show that the role of TOP motifs in translational control extends to Drosophila. Collectively, our findings reveal a nutrient-induced physiological factor that amplifies mTORC1 output in TOP mRNA translation and regulates organismal longevity.

DOI: 10.1038/s41586-026-11029-x

Source: https://www.nature.com/articles/s41586-026-11029-x