Fragile X Mental Retardation protein (FMRP), widely known for its role in hereditary intellectual disability, is an RNA-binding protein (RBP) that controls translation of select mRNAs. We discovered that endoplasmic reticulum (ER) stress induces phosphorylation of FMRP on a site that is known to enhance translation inhibition of FMRP-bound mRNAs. We show ER stress-induced activation of Inositol requiring enzyme-1 (IRE1), an ER-resident stress-sensing kinase/endoribonuclease, leads to FMRP phosphorylation and to suppression of macrophage cholesterol efflux and apoptotic cell clearance (efferocytosis). Conversely, FMRP deficiency and pharmacological inhibition of IRE1 kinase activity enhances cholesterol efflux and efferocytosis, reducing atherosclerosis in mice. Our results provide mechanistic insights into how ER stress-induced IRE1 kinase activity contributes to macrophage cholesterol homeostasis and suggests IRE1 inhibition as a promising new way to counteract atherosclerosis.

中文翻译：

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拦截 IRE1 激酶-FMRP 信号可防止动脉粥样硬化进展

脆性 X 智力迟钝蛋白 (FMRP) 因其在遗传性智力障碍中的作用而广为人知，它是一种控制选定 mRNA 翻译的 RNA 结合蛋白 (RBP)。我们发现内质网 (ER) 应激会在已知增强 FMRP 结合 mRNA 的翻译抑制作用的位点上诱导 FMRP 磷酸化。我们展示了 ER 应激诱导的肌醇需要酶 1 (IRE1) 的激活，这是一种 ER 驻留的应激感应激酶/核糖核酸内切酶，导致 FMRP 磷酸化并抑制巨噬细胞胆固醇流出和凋亡细胞清除 (胞吐作用)。相反，FMRP 缺乏和 IRE1 激酶活性的药理学抑制会增强胆固醇流出和胞吐作用，从而减少小鼠的动脉粥样硬化。