microRNA-252 and FoxO repress inflammaging by a dual inhibitory mechanism on Dawdle-mediated TGF-β pathway in Drosophila.
microRNA-252 and FoxO repress inflammaging by a dual inhibitory mechanism on Dawdle-mediated TGF-β pathway in Drosophila.
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microRNA-252 和 FoxO 通过对果蝇中 Dawdle 介导的 TGF-β 途径的双重抑制机制来抑制炎症。
DOI：
10.1093/genetics/iyab234
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发表时间：
2022
期刊：
影响因子：
3.3
通讯作者：
Liu,Nan
中科院分区：
文献类型：
--
作者：
Wu,Xiaofen;Niu,Kongyan;Wang,Xiaofan;Zhao,Jing;Wang,Han;Li,Dean;Wang,Hui;Miao,Ting;Yang,Yun;Ma,Huanhuan;Zhang,Yaoyang;Pan,Lei;Liu,Rui;Bai,Hua;Liu,Nan
炎症是指对健康寿命有有害影响的低级别、慢性激活的先天免疫。然而，人们对衰老过程中引发先天免疫基因的内在信号通路知之甚少。本研究以黑腹果蝇为研究对象，分析了幼龄和老年果蝇的microRNA靶组，揭示了TGF-β通路的激活素样配体Dawdle作为microRNA-252的生理靶点。我们发现microRNA-252与Forkhead box O（一种与衰老有关的保守转录因子）合作抑制Dawdle。无对抗的磨蹭会引发先天免疫基因的过度激活，并伴随着机体存活率的下降。利用成人肌肉组织，单细胞测序分析表明，Dawdle及其下游先天免疫基因在不同的细胞类型中表达，提示细胞非自主调节模式。我们进一步确定了Dawdle信号导致Kenny/IKKγ蛋白增加的遗传级联反应，这反过来激活了津津乐道/NF-κB蛋白和相应的先天免疫基因。最后，在野生型果蝇中转基因增加microRNA-252和Forkhead box O通路因子可以延长寿命，减轻先天免疫基因对衰老的诱导。总之，我们提出microRNA-252和Forkhead box O通过协同抑制dawdle介导的炎症来促进健康长寿。
Inflammaging refers to low-grade, chronically activated innate immunity that has deleterious effects on healthy lifespan. However, little is known about the intrinsic signaling pathway that elicits innate immune genes during aging. Here, usingDrosophila melanogaster, we profile the microRNA targetomes in young and aged animals, and reveal Dawdle, an activin-like ligand of the TGF-β pathway, as a physiological target of microRNA-252. We show that microRNA-252 cooperates with Forkhead box O, a conserved transcriptional factor implicated in aging, to repress Dawdle. Unopposed Dawdle triggers hyperactivation of innate immune genes coupled with a decline in organismal survival. Using adult muscle tissues, single-cell sequencing analysis describes that Dawdle and its downstream innate immune genes are expressed in distinct cell types, suggesting a cell nonautonomous mode of regulation. We further determine the genetic cascade by which Dawdle signaling leads to increased Kenny/IKKγ protein, which in turn activates Relish/NF-κB protein and consequentially innate immune genes. Finally, transgenic increase of microRNA-252 and Forkhead box O pathway factors in wild-typeDrosophilaextends lifespan and mitigates the induction of innate immune genes in aging. Together, we propose that microRNA-252 and Forkhead box O promote healthy longevity by cooperative inhibition on Dawdle-mediated inflammaging.