GCN2 mediates access to stored amino acids for somatic maintenance during Drosophila ageing.
GCN2 mediates access to stored amino acids for somatic maintenance during Drosophila ageing.
复制标题
GCN2 介导果蝇衰老过程中储存氨基酸的获取以维持体细胞。
DOI：
10.1101/2023.11.14.566972
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Piper,MatthewDW
中科院分区：
文献类型：
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作者：
Johnstone,JoshuaN;Mirth,ChristenK;Johnson,TravisK;Schittenhelm,RalfB;Piper,MatthewDW
许多衰老机制理论认为，体细胞维持（使用能量和资源来预防和修复细胞损伤）的逐渐失败是衰老的基础。为了维持躯体维持，生物体必须从饮食中获取数十种必需营养素，包括必需氨基酸（EAA），这对许多动物来说在生理上是有限的。在果蝇中，成年期剥夺每种 EAA 会产生截然不同的寿命轨迹，并且成年期剥夺一种 EAA（苯丙氨酸 (Phe)）不会产生相关的寿命成本；尽管每个 EAA 都严格要求生长和繁殖，但情况仍然如此。此外，在任何 EAA 剥夺下的生存完全取决于保守的 AA 传感器 GCN2，它是综合应激反应 (ISR) 的一个组成部分，这表明一种新的 ISR 介导的机制在 EAA 剥夺期间维持终生体细胞维持。在这里，我们研究了这一机制，发现长期缺乏膳食 Phe 的果蝇继续将 Phe 整合到新的蛋白质中，并且挑战果蝇增加对 Phe 的体细胞需求会缩短 Phe 缺乏下的寿命。此外，我们发现自噬是 Phe 剥夺下完整寿命所必需的，并且 ISR 的激活可以部分挽救 Phe 剥夺下 GCN2-null 缩短的寿命。因此，我们提出了一种机制，GCN2 通过 ISR 在 EAA 剥夺期间激活自噬，分解幼虫获得的 EAA 储存以支持体细胞维持。这些数据加深了我们对果蝇维持终生躯体维持策略的理解，该策略决定了响应营养环境变化的生命长度。
Many mechanistic theories of ageing argue that a progressive failure of somatic maintenance, the use of energy and resources to prevent and repair damage to the cell, underpins ageing. To sustain somatic maintenance an organism must acquire dozens of essential nutrients from the diet, including essential amino acids (EAAs), which are physiologically limiting for many animals. In Drosophila, adulthood deprivation of each individual EAA yields vastly different lifespan trajectories, and adulthood deprivation of one EAA, phenylalanine (Phe), has no associated lifespan cost; this is despite each EAA being strictly required for growth and reproduction. Moreover, survival under any EAA deprivation depends entirely on the conserved AA sensor GCN2, a component of the integrated stress response (ISR), suggesting that a novel ISR-mediated mechanism sustains lifelong somatic maintenance during EAA deprivation. Here we investigated this mechanism, finding that flies chronically deprived of dietary Phe continue to incorporate Phe into new proteins, and that challenging flies to increase the somatic requirement for Phe shortens lifespan under Phe deprivation. Further, we show that autophagy is required for full lifespan under Phe deprivation, and that activation of the ISR can partially rescue the shortened lifespan of GCN2-nulls under Phe deprivation. We therefore propose a mechanism by which GCN2, via the ISR, activates autophagy during EAA deprivation, breaking down a larvally-acquired store of EAAs to support somatic maintenance. These data refine our understanding of the strategies by which flies sustain lifelong somatic maintenance, which determines length of life in response to changes in the nutritional environment.