Role of FXR proteins in the cellular response to stress

FXR家族由三种RNA结合蛋白FXR 1、FXR 2和FMRP组成，它们的缺失导致脆性X综合征的发展，脆性X综合征是遗传性精神发育迟滞的最常见形式。这三种蛋白质普遍表达，并参与一个大的核糖核蛋白（RNP）复合物，从细胞核输出mRNA。在细胞质中，发现FXR蛋白（FXRP）与翻译多聚核糖体相关，并可激活mRNA的翻译。我已经表明，在应激条件下，哺乳动物FXRP积累到应激颗粒（SG）中;胞质体，其形成与应激后的细胞存活相关，并且mRNA翻译受到抑制。我们的工作揭示了FXRP在细胞应激反应中的新作用，通过靶向mRNA到SGs，导致其抑制。此外，我们发现FMRP的过表达诱导SGs的形成，表明FXRP在SGs成核中的作用。事实上，初步研究表明，果蝇Fmrp（dFmrp）是SG形成所需的，它由独特的同源FXR基因编码。我们假设在应激条件下，FXRP通过诱导SGs促进细胞存活。我们的总体目标是确定FXRP调节细胞应激反应的机制。为了实现这一目标，我们将致力于以下目标：I-证明FXRP在SGs形成和细胞抗应激中的作用。II-研究FXRP促进SGs形成的机制。III-确定哪些mRNA被FXRP募集到SG。IV-确定FXRP是否可以通过将关键信号蛋白隔离到SG中来促进细胞对应激介导的凋亡的抗性。

The FXR family is composed of three RNA binding proteins, FXR1, FXR2, and FMRP whose absence causes the development of Fragile X syndrome, the most common form of inherited mental retardation. The three proteins are ubiquitously expressed and participate in a large ribonucleoprotein (RNP) complex to export mRNAs from the nucleus. In the cytoplasm, FXR proteins (FXRP) are found associated with translating polyribosomes and can activate translation of mRNAs. I have shown that under stress conditions, mammalian FXRP accumulate into Stress Granules (SGs); cytoplasmic bodies, whose formation is associated with cell survival following stress and where mRNA translation is repressed. Our work revealed a new role of FXRP in cell stress response by targeting mRNAs to SGs leading to their repression. Moreover, we found that overexpression of FMRP induces the formation of SGs suggesting a role of FXRP in SGs nucleation. Indeed, pilot studies show that the drosophila Fmrp (dFmrp), which is encoded by a unique homolog FXR gene, is required for SGs formation. We hypothesize that under stress conditions FXRP promote cell survival by inducing SGs. Our overall goal is to define the mechanisms by which FXRP regulate cell stress response. To achieve this goal, we will address the following objectives: I- To demonstrate the role of FXRP in SGs formation and in cell resistance to stress. II- To investigate the mechanism(s) by which FXRP promote SGs formation. III- To determine which mRNAs are recruited by FXRP to SGs. IV-To determine whether FXRP could promote cell resistance to stress-mediated apoptosis by sequestering critical signaling proteins into SGs.