Role of FXR proteins in the cellular response to stress

FXR家族由三种RNA结合蛋白FXR1， FXR2和FMRP组成，它们的缺失会导致脆性X综合征的发展，这是遗传性智力迟钝的最常见形式。这三种蛋白无处不在地表达，并参与一个大的核糖核蛋白（RNP）复合体，从细胞核输出mrna。在细胞质中，FXR蛋白（FXRP）被发现与翻译多核糖体相关，并能激活mrna的翻译。我已经证明，在压力条件下，哺乳动物的FXRP积累成压力颗粒（SGs）；细胞质体，其形成与应激后的细胞存活有关，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，通过将mrna靶向SGs导致其抑制。此外，我们发现FMRP的过表达诱导了SGs的形成，这表明FXRP在SGs成核中的作用。事实上，初步研究表明，果蝇Fmrp （dFmrp）是SGs形成所必需的，它是由一个独特的同源FXR基因编码的。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，我们将解决以下目标：1 -证明FXRP在SGs形成和细胞抵抗压力中的作用。II-研究FXRP促进SGs形成的机制。III-确定哪些mrna被FXRP募集到SGs。目的：探讨FXRP是否通过将关键信号蛋白隔离到SGs中来促进细胞抵抗应激介导的凋亡。

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.