Bechara Elias G, Didiot Marie Cecile, Melko Mireille, Davidovic Laetitia, Bensaid Mounia, Martin Patrick, Castets Marie, Pognonec Philippe, Khandjian Edouard W, Moine Hervé, Bardoni Barbara
Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France.
PLoS Biol. 2009 Jan 20;7(1):e16. doi: 10.1371/journal.pbio.1000016.
Fragile X syndrome, the most frequent form of inherited mental retardation, is due to the absence of Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein involved in several steps of RNA metabolism. To date, two RNA motifs have been found to mediate FMRP/RNA interaction, the G-quartet and the "kissing complex," which both induce translational repression in the presence of FMRP. We show here a new role for FMRP as a positive modulator of translation. FMRP specifically binds Superoxide Dismutase 1 (Sod1) mRNA with high affinity through a novel RNA motif, SoSLIP (Sod1 mRNA Stem Loops Interacting with FMRP), which is folded as three independent stem-loop structures. FMRP induces a structural modification of the SoSLIP motif upon its interaction with it. SoSLIP also behaves as a translational activator whose action is potentiated by the interaction with FMRP. The absence of FMRP results in decreased expression of Sod1. Because it has been observed that brain metabolism of FMR1 null mice is more sensitive to oxidative stress, we propose that the deregulation of Sod1 expression may be at the basis of several traits of the physiopathology of the Fragile X syndrome, such as anxiety, sleep troubles, and autism.
脆性X综合征是遗传性智力障碍最常见的形式，它是由于缺乏脆性X智力障碍蛋白（FMRP）所致，FMRP是一种参与RNA代谢多个步骤的RNA结合蛋白。迄今为止，已发现两种RNA基序介导FMRP与RNA的相互作用，即G-四重体和“亲吻复合体”，在FMRP存在的情况下，它们都会诱导翻译抑制。我们在此展示了FMRP作为翻译正向调节因子的新作用。FMRP通过一种新的RNA基序——SoSLIP（与FMRP相互作用的Sod1 mRNA茎环），以高亲和力特异性结合超氧化物歧化酶1（Sod1）mRNA，SoSLIP折叠成三个独立的茎环结构。FMRP与SoSLIP基序相互作用时会诱导其结构修饰。SoSLIP也表现为一种翻译激活剂，其作用通过与FMRP的相互作用而增强。FMRP的缺失导致Sod1表达降低。因为已经观察到FMR1基因敲除小鼠的脑代谢对氧化应激更敏感，我们提出Sod1表达失调可能是脆性X综合征生理病理学若干特征的基础，如焦虑、睡眠障碍和自闭症。
