Davidovic Laetitia, Bechara Elias, Gravel Maud, Jaglin Xavier H, Tremblay Sandra, Sik Attila, Bardoni Barbara, Khandjian Edouard W
Unité de Recherche en Génétique Humaine et Moléculaire, Centre de recherche Hôpital Saint-François d'Assise, le CHUQ, Québec, Canada G1L 3L5.
Hum Mol Genet. 2006 May 1;15(9):1525-38. doi: 10.1093/hmg/ddl074. Epub 2006 Mar 28.
The fragile X syndrome, the leading cause of inherited mental retardation, is due to the inactivation of the fragile mental retardation 1 gene (FMR1) and the subsequent absence of its gene product FMRP. This RNA-binding protein is thought to control mRNA translation and its absence in fragile X cells leads to alteration in protein synthesis. In neurons, FMRP is thought to repress specific mRNAs during their transport as silent ribonucleoparticles (mRNPs) from the cell body to the distant synapses which are the sites of local synthesis of neuro-specific proteins. The mechanism by which FMRP sorts out its different mRNAs targets might be tuned by the intervention of different proteins. Using a yeast two-hybrid system, we identified MicroSpherule Protein 58 (MSP58) as a novel FMRP-cellular partner. In cell cultures, we found that MSP58 is predominantly present in the nucleus where it interacts with the nuclear isoform of FMRP. However, in neurons but not in glial cells, MSP58 is also present in the cytoplasmic compartment, as well as in neurites, where it co-localizes with FMRP. Biochemical evidence is given that MSP58 is associated with polyribosomal poly(A)+ mRNPs. We also show that MSP58, similar to FMRP, is present on polyribosomes prepared from synaptoneurosomes and that it behaves as an RNA-binding protein with a high affinity to the G-quartet structure. We propose that this novel cellular partner for FMRP escorts FMRP-containing mRNP from the nucleus and nucleolus to the somato-dendritic compartment where it might participate in neuronal translation regulation.
脆性X综合征是遗传性智力障碍的主要原因，它是由于脆性智力障碍1基因（FMR1）失活以及随后其基因产物FMRP缺失所致。这种RNA结合蛋白被认为可控制mRNA翻译，而其在脆性X细胞中的缺失会导致蛋白质合成改变。在神经元中，FMRP被认为在特定mRNA从细胞体作为沉默核糖核蛋白颗粒（mRNP）运输到远处突触（即神经特异性蛋白质的局部合成部位）的过程中发挥抑制作用。FMRP筛选其不同mRNA靶标的机制可能受到不同蛋白质的干预调节。利用酵母双杂交系统，我们鉴定出微球蛋白58（MSP58）是一种新的FMRP细胞伴侣。在细胞培养中，我们发现MSP58主要存在于细胞核中，并在那里与FMRP的核异构体相互作用。然而，在神经元而非神经胶质细胞中，MSP58也存在于细胞质区室以及神经突中，并与FMRP共定位。有生化证据表明MSP58与多核糖体聚（A）+ mRNP相关。我们还表明，与FMRP类似，MSP58存在于从突触小体中制备的多核糖体上，并且它表现为一种对G-四联体结构具有高亲和力的RNA结合蛋白。我们提出，这种FMRP的新细胞伴侣将含FMRP的mRNP从细胞核和核仁护送至体树突区室，在那里它可能参与神经元翻译调控。
