Department of Systems Biology and the Harvard University Wyss Institute of Biologically Inspired Engineering, Harvard Medical School, Boston, MA 02115, USA.
Mol Biol Cell. 2011 May 15;22(10):1791-805. doi: 10.1091/mbc.E10-10-0854. Epub 2011 Apr 1.
Forkhead transcription factors (FOXOs) alter a diverse array of cellular processes including the cell cycle, oxidative stress resistance, and aging. Insulin/Akt activation directs phosphorylation and cytoplasmic sequestration of FOXO away from its target genes and serves as an endpoint of a complex signaling network. Using a human genome small interfering RNA (siRNA) library in a cell-based assay, we identified an extensive network of proteins involved in nuclear export, focal adhesion, and mitochondrial respiration not previously implicated in FOXO localization. Furthermore, a detailed examination of mitochondrial factors revealed that loss of uncoupling protein 5 (UCP5) modifies the energy balance and increases free radicals through up-regulation of uncoupling protein 3 (UCP3). The increased superoxide content induces c-Jun N-terminal kinase 1 (JNK1) kinase activity, which in turn affects FOXO localization through a compensatory dephosphorylation of Akt. The resulting nuclear FOXO increases expression of target genes, including mitochondrial superoxide dismutase. By connecting free radical defense and mitochondrial uncoupling to Akt/FOXO signaling, these results have implications in obesity and type 2 diabetes development and the potential for therapeutic intervention.
叉头转录因子（FOXOs）改变了多种细胞过程，包括细胞周期、氧化应激抵抗和衰老。胰岛素/ Akt 的激活促使 FOXO 发生磷酸化，并将其从靶基因上隔离到细胞质中，这是一个复杂信号网络的终点。我们在基于细胞的测定中使用人类基因组小干扰 RNA (siRNA) 文库，鉴定出了一个涉及核输出、焦点黏附以及线粒体呼吸的广泛蛋白网络，这些蛋白以前与 FOXO 的定位无关。此外，对线粒体因子的详细检查表明，解偶联蛋白 5 (UCP5) 的缺失通过上调解偶联蛋白 3 (UCP3) 来改变能量平衡并增加自由基。增加的超氧化物含量诱导 c-Jun N-末端激酶 1 (JNK1) 激酶活性，这反过来又通过 Akt 的补偿性去磷酸化影响 FOXO 的定位。由此导致的核 FOXO 增加了靶基因的表达，包括线粒体超氧化物歧化酶。通过将自由基防御和线粒体解偶联与 Akt/FOXO 信号联系起来，这些结果与肥胖和 2 型糖尿病的发展以及治疗干预的潜力有关。
