ABSTRACT
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.
