A Putative Role for the Immunoproteasome in the Maintenance of Pluripotency in Human Embryonic Stem Cells
A Putative Role for the Immunoproteasome in the Maintenance of Pluripotency in Human Embryonic Stem Cells
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DOI：
10.1002/stem.1113
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发表时间：
2012-07-01
期刊：
影响因子：
5.2
通讯作者：
Armstrong, Lyle
中科院分区：
文献类型：
--
作者：
Atkinson, Stuart P.;Collin, Joseph;Armstrong, Lyle
蛋白酶体的功能对于维持细胞稳态至关重要，在多能干细胞中，这一功能已扩展到以限制分化的方式去除新生蛋白质。在这项研究中，我们发现人类胚胎干细胞 (hESC) 中编码 20S 蛋白酶体亚基的基因表达增强，同时随着细胞进入分化，这些基因的表达下调。对于被称为免疫蛋白酶体的 20S 蛋白酶体变体的替代催化亚基，表达的减少尤其明显，表明该蛋白酶体变体在多能细胞中可能具有迄今为止未知的功能。免疫蛋白酶体通常与抗原呈递细胞相关，为抗体生成提供适当长度的肽；然而，我们的数据表明它可能参与维持 hESC 的多能性。选择性抑制两个免疫蛋白酶体亚基（PSMB9 和 PSMB8）会导致表征多能状态的细胞表面和转录标记物下调，以牺牲 S 期为代价在 G1 期进行微妙的细胞积累，以及表征 hESC 产生的分化原始谱系和最终谱系的各种标记物的上调。我们的数据还支持 hESC 中这两个亚基各自的不同功能，这可能与其驱动蛋白酶体介导的细胞周期调节成分和/或分化诱导因子降解的选择性有关。干细胞 2012；30:1373-1384
The function of the proteasome is essential for maintenance of cellular homeostasis, and in pluripotent stem cells, this has been extended to the removal of nascent proteins in a manner that restricts differentiation. In this study, we show enhanced expression of genes encoding subunits of the 20S proteasome in human embryonic stem cells (hESCs) coupled to their downregulation as the cells progress into differentiation. The decrease in expression is particularly marked for the alternative catalytic subunits of the 20S proteasome variant known as the immunoproteasome indicating the possibility of a hitherto unknown function for this proteasome variant in pluripotent cells. The immunoproteasome is normally associated with antigen-presenting cells where it provides peptides of an appropriate length for antibody generation; however, our data suggest that it may be involved in maintaining the pluripotency in hESCs. Selective inhibition of two immunoproteasome subunits (PSMB9 and PSMB8) results in downregulation of cell surface and transcriptional markers that characterize the pluripotent state, subtle cell accumulation in G1 at the expense of S-phase, and upregulation of various markers characterizing the differentiated primitive and definitive lineages arising from hESC. Our data also support a different function for each of these two subunits in hESC that may be linked to their selectivity in driving proteasome-mediated degradation of cell cycle regulatory components and/or differentiation inducing factors. STEM CELLS 2012;30:1373-1384