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, Valášek Leoš Shivaya, Dinman Jonathan D, Zhang Youwei, Tirosh Boaz, Larsson Ola, Topisirovic Ivan, Hatzoglou Maria
Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.
Nature. 2025 Mar 26. doi: 10.1038/s41586-025-08794-6.
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). It is unclear whether impaired eIF2B activity in human diseases including leukodystrophies, 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.
真核生物翻译起始因子2亚基α（eIF2α，由EIF2S1编码；eIF2α-p）磷酸化水平升高，同时eIF2B的鸟嘌呤核苷酸交换活性降低，是“经典”整合应激反应（c-ISR）的一个标志。在包括脑白质营养不良在内的人类疾病中，eIF2B活性受损（在没有eIF2α-p诱导的情况下发生）是否与c-ISR同义尚不清楚。在这里，我们描述了一种由eIF2B活性降低触发的机制，它不同于c-ISR，我们将其称为分裂应激反应（s-ISR）。s-ISR的特征是其翻译和转录程序与c-ISR中观察到的不同。与c-ISR相反，s-ISR需要eIF4E依赖的上游开放阅读框1的翻译以及随后ATF4 mRNA的稳定。这随后导致一部分代谢基因（例如，PCK2）的表达改变，从而在eIF2B活性减弱时产生维持细胞生物能量学所需的代谢重编程。总体而言，这些数据证明了哺乳动物应激反应的可塑性，即当没有eIF2α-p诱导时eIF2B活性的丧失会激活eIF4E-ATF4-PCK2轴以维持能量稳态。
