The ER‐bound kinase/endoribonuclease (RNase), inositol‐requiring enzyme‐1 (IRE1), regulates the phylogenetically most conserved arm of the unfolded protein response (UPR). However, the complex biology and pathology regulated by mammalian IRE1 cannot be fully explained by IRE1’s one known, specific RNA target, X box‐binding protein‐1 (XBP1) or the RNA substrates of IRE1‐dependent RNA degradation (RIDD) activity. Investigating other specific substrates of IRE1 kinase and RNase activities may illuminate how it performs these diverse functions in mammalian cells. We report that macrophage IRE1 plays an unprecedented role in regulating phosphatidylinositide‐derived signaling lipid metabolites and has profound impact on the downstream signaling mediated by the mammalian target of rapamycin (mTOR). This cross‐talk between UPR and mTOR pathways occurs through the unconventional maturation of microRNA (miR) 2137 by IRE1’s RNase activity. Furthermore, phosphatidylinositol (3,4,5) phosphate (PI(3,4,5)P₃) 5‐phosphatase‐2 (INPPL1) is a direct target of miR‐2137, which controls PI(3,4,5)P₃ levels in macrophages. The modulation of cellular PI(3,4,5)P₃/PIP₂ ratio and anabolic mTOR signaling by the IRE1‐induced miR‐2137 demonstrates how the ER can provide a critical input into cell growth decisions.

中文翻译：

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肌醇需要酶 1 调节磷酸肌醇信号脂质和巨噬细胞生长

ER 结合激酶/核糖核酸内切酶 (RNase)、肌醇需要酶-1 (IRE1) 调节系统发育上最保守的未折叠蛋白反应 (UPR) 臂。然而，受哺乳动物 IRE1 调控的复杂生物学和病理学不能完全用 IRE1 的一个已知的特异性 RNA 靶标、X 框结合蛋白-1 (XBP1) 或 IRE1 依赖性 RNA 降解 (RIDD) 活性的 RNA 底物来解释。研究 IRE1 激酶和 RNase 活性的其他特定底物可能会阐明它如何在哺乳动物细胞中发挥这些不同的功能。我们报告说，巨噬细胞 IRE1 在调节磷脂酰肌醇衍生的信号转导脂质代谢物方面发挥着前所未有的作用，并对哺乳动物雷帕霉素靶蛋白 (mTOR) 介导的下游信号转导产生深远影响。UPR 和 mTOR 通路之间的这种串扰是通过 IRE1 的 RNase 活性使 microRNA (miR) 2137 非常规成熟而发生的。此外，磷脂酰肌醇 (3,4,5) 磷酸 (PI(3,4,5)P₃ ) 5-磷酸酶-2 (INPPL1) 是 miR-2137 的直接靶标，它控制巨噬细胞中的 PI(3,4,5)P ₃水平。IRE1 诱导的 miR-2137对细胞 PI(3,4,5)P ₃ /PIP ₂比率和合成代谢 mTOR 信号传导的调节表明 ER 如何为细胞生长决策提供关键输入。