EAK-7 controls development and life span by regulating nuclear DAF-16/FoxO activity.
EAK-7 controls development and life span by regulating nuclear DAF-16/FoxO activity.
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DOI：
10.1016/j.cmet.2010.05.004
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发表时间：
2010-07-07
期刊：
影响因子：
29
通讯作者：
Hu PJ
中科院分区：
文献类型：
--
作者：
Alam H;Williams TW;Dumas KJ;Guo C;Yoshina S;Mitani S;Hu PJ
FoxO转录因子控制不同物种的发育和寿命。虽然FoxO调节通过其亚细胞定位的变化是公认的，很少有人知道FoxO活性是如何在细胞核中进行调节。在这里，我们表明，保守的C。线虫蛋白EAK-7与丝氨酸/苏氨酸激酶AKT-1平行作用以抑制FoxO转录因子β-16。EAK-7活性的丧失以β-16/FoxO依赖的方式促进滞育和寿命。akt-1突变通过促进其从细胞质易位到细胞核而激活β-16/FoxO，而eak-7突变增加细胞核β-16/FoxO活性而不影响β-16/FoxO亚细胞定位。因此，EAK-7和AKT-1通过不同的机制抑制β-16/FoxO活性。我们的研究结果暗示EAK-7作为FoxO调节剂，并强调了一种新的调节途径的生物学影响，该途径在不改变其亚细胞位置的情况下控制核FoxO的活性。
FoxO transcription factors control development and longevity in diverse species. Although FoxO regulation via changes in its subcellular localization is well established, little is known about how FoxO activity is regulated in the nucleus. Here we show that the conserved C. elegans protein EAK-7 acts in parallel to the serine/threonine kinase AKT-1 to inhibit the FoxO transcription factor DAF-16. Loss of EAK-7 activity promotes diapause and longevity in a DAF-16/FoxO-dependent manner. Whereas akt-1 mutation activates DAF-16/FoxO by promoting its translocation from the cytoplasm to the nucleus, eak-7 mutation increases nuclear DAF-16/FoxO activity without influencing DAF-16/FoxO subcellular localization. Thus, EAK-7 and AKT-1 inhibit DAF-16/FoxO activity via distinct mechanisms. Our results implicate EAK-7 as a FoxO regulator and highlight the biological impact of a new regulatory pathway that governs the activity of nuclear FoxO without altering its subcellular location.
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