Role of FXR proteins in the cellular response to stress

FXR 蛋白在细胞应激反应中的作用

• 批准号: 371361-2010
• 负责人: Mazroui, Rachid
• 金额: $ 2.33万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=528186
• 关键词: Role; FXR; proteins; cellular; response

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.

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综合征的发生，脆性X综合征是最常见的遗传性智力低下形式。这三种蛋白质普遍表达，并参与一个大型核糖核蛋白(RNP)复合体，从细胞核输出mRNAs。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mRNAs的翻译。我已经证明，在应激条件下，哺乳动物的FXRP积聚成应激颗粒(SGS)，即细胞质小体，其形成与应激后细胞的存活有关，并在其中抑制mRNA的翻译。我们的工作揭示了FXRP通过将mRNA靶向SGS而在细胞应激反应中发挥新的作用，从而导致它们的抑制。此外，我们还发现FMRP的过表达诱导了SGS的形成，这表明FXRP在SGS成核中发挥了作用。事实上，初步研究表明，由独特的同源FXR基因编码的果蝇FMRP(DFmrp)是形成SGS所必需的。我们推测，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：i-展示FXRP在SGS形成和细胞抗逆性中的作用。II-探讨补肾活血方促进SGS形成的机制(S)。III-确定FXRP向SGS招募哪些mRNAs。IV-确定FXRP是否可以通过将关键信号蛋白隔离到SGS中来促进细胞对应激介导的凋亡的抵抗。