Drosophila miR-277 controls branched-chain amino acid catabolism and affects lifespan.
Drosophila miR-277 controls branched-chain amino acid catabolism and affects lifespan.
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DOI：
10.4161/rna.24810
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发表时间：
2013-06
期刊：
影响因子：
4.1
通讯作者：
Förstemann K
中科院分区：
文献类型：
--
作者：
Esslinger SM;Schwalb B;Helfer S;Michalik KM;Witte H;Maier KC;Martin D;Michalke B;Tresch A;Cramer P;Förstemann K
发育，生长和成年生存与可用的代谢资源相协调，确定有机体对环境条件的反应适当。MicroRNA是短的（21-23 nt）调节RNA，其赋予RNA诱导的沉默复合物（RISC）特异性以抑制给定的一组mRNA靶标。我们分析了果蝇成年期miRNA表达的变化，并确定miR-277在成年期下调。分子分析显示，这种miRNA控制支链氨基酸（BCAA）催化剂，因此它可以调节培养细胞中TOR激酶（一种中心生长调节因子）的活性。培养细胞和果蝇中的代谢物分析表明，机制基础可能是支链α-酮酸（BCKA）的积累，而不是BCAA，从而避免了支链氨基酸水平增加对例如，翻译保真度组成型miR-277表达缩短寿命，并且在胰岛素信号传导减少的情况下是合成致死的，表明代谢控制是这种表型的基础。使用miRNA海绵构建体的转基因抑制也会缩短寿命，特别是在富含蛋白质的食物中。因此，最佳代谢适应似乎需要通过miR-277调节细胞BCAA催化剂。
Development, growth and adult survival are coordinated with available metabolic resources, ascertaining that the organism responds appropriately to environmental conditions. MicroRNAs are short (21–23 nt) regulatory RNAs that confer specificity on the RNA-induced silencing complex (RISC) to inhibit a given set of mRNA targets. We profiled changes in miRNA expression during adult life in Drosophila melanogaster and determined that miR-277 is downregulated during adult life. Molecular analysis revealed that this miRNA controls branched-chain amino acid (BCAA) catabolism and as a result it can modulate the activity of the TOR kinase, a central growth regulator, in cultured cells. Metabolite analysis in cultured cells as well as flies suggests that the mechanistic basis may be an accumulation of branched-chain α-keto-acids (BCKA), rather than BCAAs, thus avoiding potentially detrimental consequences of increased branched chain amino acid levels on e.g., translational fidelity. Constitutive miR-277 expression shortens lifespan and is synthetically lethal with reduced insulin signaling, indicating that metabolic control underlies this phenotype. Transgenic inhibition with a miRNA sponge construct also shortens lifespan, in particular on protein-rich food. Thus, optimal metabolic adaptation appears to require tuning of cellular BCAA catabolism by miR-277.
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影响因子：
64.8
作者：
Baek, Daehyun;Villen, Judit;Shin, Chanseok;Camargo, Fernando D.;Gygi, Steven P.;Bartel, David P.
通讯作者：
Bartel, David P.
影响因子：
29
作者：
Cochemé HM;Quin C;McQuaker SJ;Cabreiro F;Logan A;Prime TA;Abakumova I;Patel JV;Fearnley IM;James AM;Porteous CM;Smith RA;Saeed S;Carré JE;Singer M;Gems D;Hartley RC;Partridge L;Murphy MP
通讯作者：
Murphy MP
影响因子：
4.1
作者：
Beitzinger, Michaela;Peters, Lasse;Meister, Gunter
通讯作者：
Meister, Gunter
影响因子：
9.2
作者：
Brogiolo, W;Stocker, H;Hafen, E
通讯作者：
Hafen, E
影响因子：
4.5
作者：
Easow, George;Teleman, Aurelio A.;Cohen, Stephen M.
通讯作者：
Cohen, Stephen M.