Nrf2, a regulator of the proteasome, controls self-renewal and pluripotency in human embryonic stem cells.
Nrf2, a regulator of the proteasome, controls self-renewal and pluripotency in human embryonic stem cells.
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DOI：
10.1002/stem.1764
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发表时间：
2014-10
期刊：
影响因子：
5.2
通讯作者：
Kosik, Kenneth S.
中科院分区：
文献类型：
--
作者：
Jang, Jiwon;Wang, Yidi;Kim, Hyung-Seok;Lalli, Matthew A.;Kosik, Kenneth S.
核因子，红系2样蛋白2(Nrf2)是一种主要的转录因子，通过调节多种抗氧化和解毒基因的表达，为细胞抵御内源和外源应激而发挥作用。在这里，我们发现Nrf2在人类胚胎干细胞(HESCs)中是一个关键的多能性基因和蛋白酶体活性的调节因子。在hESCs中，Nrf2的表达高度丰富，分化后显著降低。抑制NRF2既损害了hESCs的自我更新能力，也损害了细胞重编程过程中多能性的重建。NRF2的激活可以延缓分化。在hESC分化早期，Nrf2与OCT4和NANOG紧密共定位。作为一个潜在的机制，我们的数据表明，Nrf2部分地通过蛋白酶体成熟蛋白(POMP)调节hESCs的蛋白酶体活性，蛋白酶体成熟蛋白(POMP)是一种蛋白酶体伴侣蛋白，它反过来控制自我更新的hESCs的增殖、三胚层分化和细胞重编程。即使是适度的蛋白酶体抑制，也会降低细胞周期蛋白D1的蛋白水平，延缓OCT4和NANOG蛋白的降解，从而以牺牲外胚层命运为代价，扭曲早期向中胚层分化的平衡。综上所述，我们的发现表明，环境胁迫和茎干之间存在一种新的潜在联系，Nrf2和蛋白酶体被协调定位为关键的调节因子。
Nuclear factor, erythroid 2-like 2 (Nrf2) is a master transcription factor for cellular defense against endogenous and exogenous stresses by regulating expression of many antioxidant and detoxification genes. Here, we show that Nrf2 acts as a key pluripotency gene and a regulator of proteasome activity in human embryonic stem cells (hESCs). Nrf2 expression is highly enriched in hESCs and dramatically decreases upon differentiation. Nrf2 inhibition impairs both the self-renewal ability of hESCs and reestablishment of pluripotency during cellular reprogramming. Nrf2 activation can delay differentiation. During early hESC differentiation, Nrf2 closely co-localizes with OCT4 and NANOG. As an underlying mechanism, our data show that Nrf2 regulates proteasome activity in hESCs partially through proteasome maturation protein (POMP), a proteasome chaperone, which in turn controls the proliferation of self-renewing hESCs, three germ layer differentiation and cellular reprogramming. Even modest proteasome inhibition skews the balance of early differentiation toward mesendoderm at the expense of an ectodermal fate by decreasing the protein level of cyclin D1 and delaying the degradation of OCT4 and NANOG proteins. Taken together, our findings suggest a new potential link between environmental stress and stemness with Nrf2 and the proteasome coordinately positioned as key mediators.
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作者：
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