Role of FXR proteins in the cellular response to stress

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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.