Thakar Nilay Yogeshkumar, Ovchinnikov Dmitry Alexander, Hastie Marcus Lachlan, Gorman Jeffrey, Wolvetang Ernst Jurgen
1 Stem Cell Engineering Group, Australian Institute for Bioengineering and Nanotechnology, The University of Queensland , St. Lucia, QLD, Australia .
2 Protein Discovery Centre, QIMR Berghofer Medical Research Institute , Herston, QLD, Australia .
Stem Cells Dev. 2015 Aug 15;24(16):1888-900. doi: 10.1089/scd.2014.0587. Epub 2015 May 5.
The molecular mechanisms that orchestrate the exit from pluripotency, cell cycle progression, and lineage-specific differentiation in human pluripotent stem cells (hPSCs) are poorly understood. RELB, a key protein in the noncanonical nuclear factor-kappaB (NFκB) signaling pathway, was previously implicated in controlling the switch between human embryonic stem cell (hESC) proliferation and differentiation. Here, we show that RELB enhances the proliferation of hESCs and human-induced pluripotent stem cells (hiPSCs) without affecting their pluripotency. We demonstrate that RELB does this by interacting with two RNA-binding proteins LIN28A and IMP3 (IGF2 mRNA-binding protein 3); further, these interactions control mRNA levels and protein expression of insulin-like growth factor 2 (IGF2) and key cell-cycle genes. Finally, after stress, these proteins co-localize in stress granules in hESCs and iPSCs. Our data identify RELB as a novel regulator of hPSC proliferation, and suggest a new function for RELB, in addition to its widely accepted role as a transcription factor, that involves recruitment of IMP3 and LIN28 to the cytosolic mRNA translation-control domains for post-transcriptional modulation of IGF2 and cell-cycle gene expression.
协调人类多能干细胞（hPSC）退出多能性、细胞周期进程和谱系特异性分化的分子机制仍知之甚少。RELB是非经典核因子κB（NFκB）信号通路中的关键蛋白，此前被认为参与控制人类胚胎干细胞（hESC）增殖与分化之间的转换。在此，我们表明RELB可增强hESC和人类诱导多能干细胞（hiPSC）的增殖，而不影响其多能性。我们证明RELB通过与两种RNA结合蛋白LIN28A和IMP3（胰岛素样生长因子2信使核糖核酸结合蛋白3）相互作用来实现这一点；此外，这些相互作用控制胰岛素样生长因子2（IGF2）和关键细胞周期基因的mRNA水平及蛋白质表达。最后，在应激后，这些蛋白在hESC和iPSC的应激颗粒中共定位。我们的数据确定RELB是hPSC增殖的新型调节因子，并表明RELB除了作为转录因子这一被广泛认可的作用外，还具有新功能，即招募IMP3和LIN28至胞质mRNA翻译控制域，以对IGF2和细胞周期基因表达进行转录后调控。
