Hydrogen peroxide (HO) functions as a signaling molecule in diverse cellular processes. While cells have evolved the capability to detect and manage changes in HO levels, the mechanisms regulating key HO-producing enzymes to maintain optimal levels, especially in pancreatic beta cells with notably weak antioxidative defense, remain unclear. We found that the protein EI24 responds to changes in HO concentration and regulates the production of HO by controlling the translation of NOX4, an enzyme that is constitutively active, achieved by recruiting an RNA-binding protein, RTRAF, to the 3′-UTR of . Depleting EI24 results in RTRAF relocating into the nucleus, releasing the brake on NOX4 translation. The excessive production of HO by liberated NOX4 further suppresses the translation of the key transcription factor , ultimately preventing its binding to the gene promoter and subsequent transcription of insulin. Treatment with a specific NOX4 inhibitor or the antioxidant NAC reversed these effects and alleviated the diabetic symptoms in beta-cell specific -KO mice. This study revealed a new mechanism through which cells regulate oxidative stress at the translational level, involving an ER-tethered RNA-binding protein that controls the expression of the key HO-producing enzyme NOX4.

中文翻译：

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内质网束缚的 RNA 结合蛋白控制 NADPH 氧化酶翻译以实现过氧化氢稳态


过氧化氢 (H2O) 在多种细胞过程中充当信号分子。虽然细胞已经进化出检测和管理 H2O2 水平变化的能力，但调节关键 H2O2 产生酶以维持最佳水平的机制仍不清楚，特别是在抗氧化防御明显较弱的胰腺β细胞中。我们发现蛋白质 EI24 对 H2O 浓度的变化做出反应，并通过控制 NOX4 的翻译来调节 H2O 的产生，NOX4 是一种组成型活性酶，通过将 RNA 结合蛋白 RTRAF 募集到 H2O 的 3'-UTR 来实现。 。耗尽 EI24 会导致 RTRAF 重新定位到细胞核中，从而释放对 NOX4 翻译的抑制。释放的 NOX4 过量产生 H2O 进一步抑制关键转录因子的翻译，最终阻止其与基因启动子结合以及随后的胰岛素转录。使用特定的 NOX4 抑制剂或抗氧化剂 NAC 治疗可以逆转这些效应，并减轻 β 细胞特异性 -KO 小鼠的糖尿病症状。这项研究揭示了细胞在翻译水平上调节氧化应激的新机制，涉及一种内质网束缚的RNA结合蛋白，该蛋白控制关键的H2O产生酶NOX4的表达。