College of Life Science and Technology, College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, China.
Hubei Cancer Hospital (HBCH), Wuhan, 430079, China.
Cell Death Dis. 2022 May 14;13(5):459. doi: 10.1038/s41419-022-04897-4.
Hypoxia modulates senescence, but their physiological link remains unclear. Here, we found that eIF4E2, a hypoxia-activated translation initiation factor, interacted with GSK3β to maintain phosphorylation of p53, thus resisting senescence under hypoxia. RNA-binding protein RBM38 interacted with eIF4E to inhibit the translation of p53, but GSK3β-mediated Ser195 phosphorylation disrupted the RBM38-eIF4E interaction. Through investigation of RBM38 phosphorylation, we found that the eIF4E2-GSK3β pathway specifically regulated proline-directed serine/threonine phosphorylation (S/T-P). Importantly, peptides e2-I or G3-I that blocking eIF4E2-GSK3β interaction can inhibit the basal S/T-P phosphorylation of p53 at multiple sites, therby inducing senescence through transcriptional inhibition. Additionally, a nanobody was screened via the domain where eIF4E2 bound to GSK3β, and this nanobody inhibited S/T-P phosphorylation to promote senescence. Furthermore, hypoxia inhibited eIF4E2-GSK3β pathway by mediating S-Nitrosylation of GSK3β. Blocking eIF4E2-GSK3β interaction promoted liver senescence under hypoxia, thus leading to liver fibrosis, eventually accelerating N, N-diethylnitrosamine (DEN)-induced tumorigenesis. Interestingly, eIF4E2 isoforms with GSK3β-binding motif exclusively exist in mammals, which protect zebrafish heart against hypoxia. Together, this study reveals a mammalian eIF4E2-GSK3β pathway that prevents senescence by maintaining basal S/T-P phosphorylation of p53, which underlies hypoxia adaptation of tissues.
缺氧调节衰老，但它们的生理联系尚不清楚。在这里，我们发现缺氧激活的翻译起始因子 eIF4E2 与 GSK3β 相互作用，以维持 p53 的磷酸化，从而在缺氧下抵抗衰老。RNA 结合蛋白 RBM38 与 eIF4E 相互作用，抑制 p53 的翻译，但 GSK3β 介导的 Ser195 磷酸化破坏了 RBM38-eIF4E 相互作用。通过对 RBM38 磷酸化的研究，我们发现 eIF4E2-GSK3β 途径特异性调节脯氨酸导向的丝氨酸/苏氨酸磷酸化 (S/T-P)。重要的是，阻断 eIF4E2-GSK3β 相互作用的肽 e2-I 或 G3-I 可以抑制 p53 在多个位点的基础 S/T-P 磷酸化，从而通过转录抑制诱导衰老。此外，通过 eIF4E2 与 GSK3β 结合的结构域筛选出一种纳米抗体，该纳米抗体抑制 S/T-P 磷酸化以促进衰老。此外，缺氧通过介导 GSK3β 的 S-亚硝基化来抑制 eIF4E2-GSK3β 途径。阻断 eIF4E2-GSK3β 相互作用促进缺氧下的肝衰老，从而导致肝纤维化，最终加速 N，N-二乙基亚硝胺 (DEN) 诱导的肿瘤发生。有趣的是，具有 GSK3β 结合基序的 eIF4E2 同工型仅存在于哺乳动物中，它们保护斑马鱼心脏免受缺氧的影响。总之，这项研究揭示了一种哺乳动物 eIF4E2-GSK3β 途径，通过维持 p53 的基础 S/T-P 磷酸化来防止衰老，这是组织适应缺氧的基础。
