凯斯西储大学Maria Hatzoglou团队取得一项新突破。他们报道了哺乳动物综合应激反应的可塑性。相关论文发表在2025年3月26日出版的《自然》杂志上。

在这里，研究小组描述了一种由eIF2B活性降低触发的机制，不同于c-ISR，研究小组称之为分裂ISR （s-ISR）。s-ISR的特点是翻译和转录程序不同于c-ISR。与c-ISR相反，s-ISR需要上游开放阅读框1依赖eIF4E的翻译和随后的ATF4 mRNA稳定。随后是代谢基因子集（例如PCK2）的表达改变，导致在eIF2B活性减弱时维持细胞生物能量所需的代谢重新布线。总的来说，这些数据证明了哺乳动物ISR的可塑性，即在缺乏eIF2α-p诱导的情况下，eIF2B活性的丧失激活了eIF4E-ATF4-PCK2轴以维持能量稳态。

据介绍，EIF2S1编码的真核翻译起始因子2亚单位-α (eIF2α)磷酸化水平升高；eIF2α-p)与eIF2B的鸟嘌呤核苷酸交换活性降低是“典型”综合应激反应（c-ISR）的标志。目前尚不清楚，在没有eIF2α-p诱导的情况下，包括白质营养不良在内的人类疾病中，eIF2B活性受损是否与c-ISR同义。

附：英文原文

Title: Plasticity of the mammalian integrated stress response

Author: Chen, Chien-Wen, Papadopoli, David, Szkop, Krzysztof J., Guan, Bo-Jhih, Alzahrani, Mohammed, Wu, Jing, Jobava, Raul, Asraf, Mais M., Krokowski, Dawid, Vourekas, Anastasios, Merrick, William C., Komar, Anton A., Koromilas, Antonis E., Gorospe, Myriam, Payea, Matthew J., Wang, Fangfang, Clayton, Benjamin L. L., Tesar, Paul J., Schaffer, Ashleigh, Miron, Alexander, Bederman, Ilya, Jankowsky, Eckhard, Vogel, Christine, Valek, Leo Shivaya, Dinman, Jonathan D., Zhang, Youwei, Tirosh, Boaz, Larsson, Ola, Topisirovic, Ivan, Hatzoglou, Maria

Issue&Volume: 2025-03-26

Abstract: An increased level of phosphorylation of eukaryotic translation initiation factor 2 subunit-α (eIF2α, encoded by EIF2S1; eIF2α-p) coupled with decreased guanine nucleotide exchange activity of eIF2B is a hallmark of the ‘canonical’ integrated stress response (c-ISR)1. It is unclear whether impaired eIF2B activity in human diseases including leukodystrophies2, which occurs in the absence of eIF2α-p induction, is synonymous with the c-ISR. Here we describe a mechanism triggered by decreased eIF2B activity, distinct from the c-ISR, which we term the split ISR (s-ISR). The s-ISR is characterized by translational and transcriptional programs that are different from those observed in the c-ISR. Opposite to the c-ISR, the s-ISR requires eIF4E-dependent translation of the upstream open reading frame 1 and subsequent stabilization of ATF4 mRNA. This is followed by altered expression of a subset of metabolic genes (for example, PCK2), resulting in metabolic rewiring required to maintain cellular bioenergetics when eIF2B activity is attenuated. Overall, these data demonstrate a plasticity of the mammalian ISR, whereby the loss of eIF2B activity in the absence of eIF2α-p induction activates the eIF4E–ATF4–PCK2 axis to maintain energy homeostasis.

DOI: 10.1038/s41586-025-08794-6

Source: https://www.nature.com/articles/s41586-025-08794-6