Termination of the integrated stress response
Summary
Stress responses enable cells to detect, adapt to, and survive challenges. The benefit of these signaling pathways depends on their reversibility. The integrated stress response (ISR) is elicited by phosphorylation of eukaryotic translation initiation factor eIF2, which traps and inhibits rate-limiting translation factor eIF2B, thereby attenuating translation initiation. Termination of this pathway thus requires relieving eIF2B from P-eIF2 inhibition. Here, we found that eIF2 phosphatase s
Content
# Termination of the integrated stress response
*Published: 2026 Feb 19*
Stress responses enable cells to detect, adapt to, and survive challenges. The
benefit of these signaling pathways depends on their reversibility. The
integrated stress response (ISR) is elicited by phosphorylation of eukaryotic
translation initiation factor eIF2, which traps and inhibits rate-limiting
translation factor eIF2B, thereby attenuating translation initiation.
Termination of this pathway thus requires relieving eIF2B from P-eIF2
inhibition. Here, we found that eIF2 phosphatase subunits PPP1R15A and PPP1R15B
(R15B) bound P-eIF2 in complex with eIF2B. Biochemical investigations guided by
cryo-electron microscopy structures of native eIF2-eIF2B and P-eIF2-eIF2B
complexes bound to R15B demonstrated that R15B enabled dephosphorylation of
otherwise dephosphorylation-incompetent P-eIF2 on eIF2B. This sheds light on ISR
termination, revealing that R15B rescues eIF2B from P-eIF2 inhibition, thereby
safeguarding translation and cell fitness.
DOI: 10.1126/science.adw5137