UBR-5 and UBE2D mediate timely exit from stem fate via destabilization of poly(A)-binding protein PABP-2 in cell state transition.

Abstract

UBR5 E3 ligase has been associated with cancer susceptibility and neuronal integrity, with functions in chromatin regulation and proteostasis. However, the functions of <i>ubr5</i> within animals remain unclear due to lethality in both mammals and flies when disrupted. Using <i>Caenorhabditis elegans</i>, we show that UBR-5 E3 ligase is required for timely exit of stem fate and complete transition into multiple cell type descendants in an ectodermal blast lineage. Animals lacking intact UBR-5 function simultaneously exhibit both stem fate and differentiated fate in the same descendant cells. A functional screen of UBR-5 physical interactors allowed us to identify the UBE2D2/3 E2 conjugase LET-70 working with UBR-5 to exit stem fate. Strikingly, we revealed that another UBR-5 physical interactor, namely the nuclear poly(A)-binding protein PABPN1 ortholog PABP-2, worked antagonistically to UBR-5 and LET-70. Lowering <i>pabp-2</i> levels restored normal transition of cell state out of stemness and promoted normal cell fusion when either <i>ubr-5</i> or <i>let-70</i> UBE2D function was compromised. The UBR-5-LET-70 and PABP-2 switch works independently of the stem pool size determined by pluripotency factors like <i>lin-28.</i> UBR-5 limits PABP-2 protein and reverses the PABP-2-dependent gene expression program including developmental, proteostasis, and innate immunity genes. Loss of <i>ubr-5</i> rescues the developmental stall when <i>pabp-2</i> is compromised. Disruption of <i>ubr-5</i> elevates PABP-2 levels and prolongs expression of ectodermal and muscle stem markers at the transition to adulthood. Additionally, <i>ubr-5</i> mutants exhibit an extended period of motility during aging and suppress <i>pabp-2-</i>dependent early onset of immobility.