The nuclear cap-binding complex safeguards stress-resistant protein synthesis and proliferation of stem cells [Ribo-seq]

A caveat is that essential proteins for cell survival or maintenance should be expressed even under ISR-activated conditions. Here, we find that when global translation is compromised due to eIF2α phosphorylation during ISR, eIF2A takes over the function of eIF2α for Met-tRNAi delivery.

Notably, preferential association between eIF2A and cellular factors involved in the pioneer round of translation driven by nuclear cap-binding protein complex (CBP20/80) allows the pioneer translation to occur during ISR. We also observe that ISR is activated in growing human embryonic stem cell (hESC) colonies. Under these naturally arising ISR conditions, eIF2A-mediated pioneer translation is active and safeguards self-renewal and differentiation of hESCs.