A TORC1-histone axis regulates chromatin organisation and non-canonical induction of autophagy to ameliorate ageing.
A TORC1-histone axis regulates chromatin organisation and non-canonical induction of autophagy to ameliorate ageing.
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DOI：
10.7554/elife.62233
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发表时间：
2021-05-14
期刊：
影响因子：
7.7
通讯作者：
Partridge L
中科院分区：
文献类型：
--
作者：
Lu YX;Regan JC;Eßer J;Drews LF;Weinseis T;Stinn J;Hahn O;Miller RA;Grönke S;Partridge L
在许多物种中都观察到组蛋白水平与年龄相关的变化。然而，目前尚不清楚组蛋白表达的变化是否可以用来改善多细胞生物体衰老的影响。在这里，我们发现延长寿命的药物雷帕霉素对 mTORC1 的抑制作用通过 eIF3 介导的翻译增加了转录后组蛋白 H3 和 H4 的表达。果蝇肠上皮细胞中 H3/H4 表达升高会改变染色质组织，通过转录调节诱导肠道自噬，并防止肠道随年龄增长而衰退。重要的是，它还介导雷帕霉素诱导的长寿和肠道健康。组蛋白 H3/H4 调节自噬货物接头 Bchs（哺乳动物中的 WDFY3）的表达，其在肠上皮细胞中的表达增加可介导 H3/H4 依赖性健康寿命的延长。在小鼠中，雷帕霉素治疗增加了组蛋白的表达和 Wdfy3 转录，并改变了小肠中的染色质组织，表明 mTORC1-组蛋白轴在哺乳动物中至少部分保守，并可能为抗衰老干预提供新的靶点。
Age-related changes to histone levels are seen in many species. However, it is unclear whether changes to histone expression could be exploited to ameliorate the effects of ageing in multicellular organisms. Here we show that inhibition of mTORC1 by the lifespan-extending drug rapamycin increases expression of histones H3 and H4 post-transcriptionally through eIF3-mediated translation. Elevated expression of H3/H4 in intestinal enterocytes in Drosophila alters chromatin organisation, induces intestinal autophagy through transcriptional regulation, and prevents age-related decline in the intestine. Importantly, it also mediates rapamycin-induced longevity and intestinal health. Histones H3/H4 regulate expression of an autophagy cargo adaptor Bchs (WDFY3 in mammals), increased expression of which in enterocytes mediates increased H3/H4-dependent healthy longevity. In mice, rapamycin treatment increases expression of histone proteins and Wdfy3 transcription, and alters chromatin organisation in the small intestine, suggesting that the mTORC1-histone axis is at least partially conserved in mammals and may offer new targets for anti-ageing interventions.
影响因子：
9.9
作者：
Tain LS;Sehlke R;Jain C;Chokkalingam M;Nagaraj N;Essers P;Rassner M;Grönke S;Froelich J;Dieterich C;Mann M;Alic N;Beyer A;Partridge L
通讯作者：
Partridge L