近日，Anne Bertolotti及其研究组提出了终止综合应力响应。该项研究成果发表在2025年11月13日出版的《科学》上。

课题组发现eIF2磷酸酶亚基PPP1R15A和PPP1R15B （R15B）与eIF2B复合物结合P-eIF2。结合R15B的天然eIF2-eIF2B和P-eIF2-eIF2B复合物的低温电镜结构指导下的生化研究表明，R15B能够使eIF2B上不去磷酸化的P-eIF2去磷酸化。这揭示了ISR的终止，揭示了R15B从P-eIF2抑制中拯救eIF2B，从而保护翻译和细胞适应性。

据了解，应激反应使细胞能够检测、适应和生存挑战。这些信号通路的好处取决于它们的可逆性。综合应激反应（integrated stress response， ISR）是由翻译起始因子eIF2的磷酸化引起的，该磷酸化捕获并抑制限速翻译因子eIF2B，从而减弱翻译起始。终止这一途径需要解除eIF2B对P-eIF2的抑制。

附：英文原文

Title: Termination of the integrated stress response

Author: Claudia De Miguel, Sigurdur R. Thorkelsson, Agnieszka Fatalska, George Hodgson, Chao Wang, Anne Bertolotti

Issue&Volume: 2025-11-13

Abstract: 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 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-EM 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: adw5137

Source: https://www.science.org/doi/10.1126/science.adw5137