Didiot Marie-Cécile, Subramanian Murugan, Flatter Eric, Mandel Jean-Louis, Moine Hervé
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université Louis Pasteur, Collège de France, Chaire de Génétique Humaine, Illkirch-Graffenstaden, France.
Mol Biol Cell. 2009 Jan;20(1):428-37. doi: 10.1091/mbc.e08-07-0737. Epub 2008 Nov 12.
The fragile X mental retardation protein (FMRP) is an RNA-binding protein involved in the mRNA metabolism. The absence of FMRP in neurons leads to alterations of the synaptic plasticity, probably as a result of translation regulation defects. The exact molecular mechanisms by which FMRP plays a role in translation regulation have remained elusive. The finding of an interaction between FMRP and the RNA interference silencing complex (RISC), a master of translation regulation, has suggested that both regulators could be functionally linked. We investigated here this link, and we show that FMRP exhibits little overlap both physically and functionally with the RISC machinery, excluding a direct impact of FMRP on RISC function. Our data indicate that FMRP and RISC are associated to distinct pools of mRNAs. FMRP, unlike RISC machinery, associates with the pool of mRNAs that eventually goes into stress granules upon cellular stress. Furthermore, we show that FMRP plays a positive role in this process as the lack of FMRP or a point mutant causing a severe fragile X alter stress granule formation. Our data support the proposal that FMRP plays a role in controlling the fate of mRNAs after translation arrest.
脆性X智力低下蛋白（FMRP）是一种参与mRNA代谢的RNA结合蛋白。神经元中缺乏FMRP会导致突触可塑性改变，这可能是翻译调控缺陷的结果。FMRP在翻译调控中发挥作用的确切分子机制仍然不清楚。FMRP与翻译调控的主要因子RNA干扰沉默复合体（RISC）之间存在相互作用，这表明这两种调控因子在功能上可能存在联系。我们在此研究了这种联系，结果表明FMRP在物理和功能上与RISC机制几乎没有重叠，排除了FMRP对RISC功能的直接影响。我们的数据表明，FMRP和RISC与不同的mRNA池相关联。与RISC机制不同，FMRP与细胞应激时最终进入应激颗粒的mRNA池相关联。此外，我们表明FMRP在此过程中发挥积极作用，因为缺乏FMRP或导致严重脆性X的点突变会改变应激颗粒的形成。我们的数据支持了FMRP在翻译停滞后控制mRNA命运中发挥作用的观点。
