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

The integrated stress response (ISR) suppresses global translation while allowing selective synthesis of key regulatory proteins. However, how translation persists during ISR remains unclear. In eukaryotes, the 5'-cap of mRNAs is bound by either the cap-binding complex (CBC) or eIF4E. We show that under stress, CBC-bound mRNAs recruit eIF2A, an alternative initiation factor, to sustain translation when eIF4E-dependent translation is inhibited. Human embryonic stem cells (hESCs), which inherently exhibit ISR, continue proliferating due to a compensatory increase in eIF2A. This increase ensures CBC-dependent translation (CT) of essential cell cycle regulators. Notably, yes-associated protein (YAP), a key proliferation factor, is a major CT target driving stress-resistant stem cell proliferation. Our findings reveal CT as a critical pathway that preserves protein synthesis and proliferation under stress.