Howard Hughes Medical Institute, Glenn Center for Aging Research, Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Nature. 2012 Sep 13;489(7415):304-8. doi: 10.1038/nature11468.
Embryonic stem cells can replicate continuously in the absence of senescence and, therefore, are immortal in culture. Although genome stability is essential for the survival of stem cells, proteome stability may have an equally important role in stem-cell identity and function. Furthermore, with the asymmetric divisions invoked by stem cells, the passage of damaged proteins to daughter cells could potentially destroy the resulting lineage of cells. Therefore, a firm understanding of how stem cells maintain their proteome is of central importance. Here we show that human embryonic stem cells (hESCs) exhibit high proteasome activity that is correlated with increased levels of the 19S proteasome subunit PSMD11 (known as RPN-6 in Caenorhabditis elegans) and a corresponding increased assembly of the 26S/30S proteasome. Ectopic expression of PSMD11 is sufficient to increase proteasome assembly and activity. FOXO4, an insulin/insulin-like growth factor-I (IGF-I) responsive transcription factor associated with long lifespan in invertebrates, regulates proteasome activity by modulating the expression of PSMD11 in hESCs. Proteasome inhibition in hESCs affects the expression of pluripotency markers and the levels of specific markers of the distinct germ layers. Our results suggest a new regulation of proteostasis in hESCs that links longevity and stress resistance in invertebrates to hESC function and identity.
胚胎干细胞在不存在衰老的情况下可以连续复制，因此在培养中是永生的。尽管基因组稳定性对于干细胞的存活至关重要，但蛋白质组稳定性在干细胞特性和功能中可能具有同样重要的作用。此外，由于干细胞的不对称分裂，受损蛋白质传递给子细胞可能会破坏产生的细胞谱系。因此，深入了解干细胞如何维持其蛋白质组至关重要。在这里，我们表明人类胚胎干细胞 (hESC) 表现出高蛋白酶体活性，这与 19S 蛋白酶体亚基 PSMD11（在秀丽隐杆线虫中称为 RPN-6）的水平升高以及 26S/30S 蛋白酶体的相应组装增加有关。PSMD11 的异位表达足以增加蛋白酶体的组装和活性。FOXO4 是一种与无脊椎动物长寿命相关的胰岛素/胰岛素样生长因子-I (IGF-I) 反应转录因子，通过调节 hESC 中 PSMD11 的表达来调节蛋白酶体活性。在 hESC 中抑制蛋白酶体活性会影响多能性标志物的表达以及不同胚层的特定标志物的水平。我们的研究结果表明，在 hESC 中存在一种新的蛋白质稳定性调节，它将无脊椎动物中的长寿和抗应激与 hESC 功能和特性联系起来。
