Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen-Strasse 25, München, Germany.
RNA Biol. 2013 Jun;10(6):1042-56. doi: 10.4161/rna.24810. Epub 2013 Apr 30.
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.
发育、生长和成年后的存活与可用的代谢资源相协调，以确保生物体能对环境条件做出适当的反应。microRNA 是一类短链（21-23 个核苷酸）的调控 RNA，能使 RNA 诱导沉默复合物（RISC）特异性地抑制特定的一组 mRNA 靶标。我们对黑腹果蝇成年后的 miRNA 表达变化进行了分析，发现 miR-277 在成年后下调。分子分析表明，这种 miRNA 控制支链氨基酸（BCAA）的分解代谢，因此可以在培养的细胞中调节 TOR 激酶的活性，TOR 激酶是一种中央生长调节剂。在培养的细胞和果蝇中的代谢物分析表明，其作用机制可能是支链α-酮酸（BCKA）的积累，而不是 BCAA，从而避免增加支链氨基酸水平对例如翻译保真度的潜在不利影响。组成型表达 miR-277 会缩短寿命，与降低胰岛素信号通路协同作用会导致合成致死，表明这种表型是由代谢控制引起的。用 miRNA 海绵构建体进行转基因抑制也会缩短寿命，特别是在富含蛋白质的食物上。因此，最佳的代谢适应似乎需要 miR-277 来调节细胞内的 BCAA 分解代谢。
