Laboratory of Cellular and Molecular Biology, National Institute on Aging Intramural Research Program, US National Institutes of Health, Baltimore, Maryland, USA.
Nat Struct Mol Biol. 2010 Jun;17(6):732-9. doi: 10.1038/nsmb.1815. Epub 2010 May 16.
Amyloid precursor protein (APP) regulates neuronal synapse function, and its cleavage product Abeta is linked to Alzheimer's disease. Here, we present evidence that the RNA-binding proteins (RBPs) heterogeneous nuclear ribonucleoprotein (hnRNP) C and fragile X mental retardation protein (FMRP) associate with the same APP mRNA coding region element, and they influence APP translation competitively and in opposite directions. Silencing hnRNP C increased FMRP binding to APP mRNA and repressed APP translation, whereas silencing FMRP enhanced hnRNP C binding and promoted translation. Repression of APP translation was linked to colocalization of FMRP and tagged APP RNA within processing bodies; this colocalization was abrogated by hnRNP C overexpression or FMRP silencing. Our findings indicate that FMRP represses translation by recruiting APP mRNA to processing bodies, whereas hnRNP C promotes APP translation by displacing FMRP, thereby relieving the translational block.
淀粉样前体蛋白(APP)调节神经元突触功能,其裂解产物 Abeta 与阿尔茨海默病有关。在这里,我们提供的证据表明,RNA 结合蛋白(RBPs)异质核核糖核蛋白(hnRNP)C 和脆性 X 智力迟钝蛋白(FMRP)与相同的 APP mRNA 编码区元件结合,它们以竞争和相反的方式影响 APP 翻译。沉默 hnRNP C 增加了 FMRP 与 APP mRNA 的结合并抑制了 APP 翻译,而沉默 FMRP 增强了 hnRNP C 的结合并促进了翻译。APP 翻译的抑制与加工体中 FMRP 和标记的 APP RNA 的共定位有关;hnRNP C 过表达或 FMRP 沉默消除了这种共定位。我们的研究结果表明,FMRP 通过将 APP mRNA 募集到加工体中来抑制翻译,而 hnRNP C 通过置换 FMRP 来促进 APP 翻译,从而解除翻译阻断。