Neurodegeneration-associated TDP-43 Interacts with Fragile X Mental Retardation Protein (FMRP)/Staufen (STAU1) and Regulates SIRT1 Expression in Neuronal Cells*
Neurodegeneration-associated TDP-43 Interacts with Fragile X Mental Retardation Protein (FMRP)/Staufen (STAU1) and Regulates SIRT1 Expression in Neuronal Cells*
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DOI：
10.1074/jbc.m112.357582
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发表时间：
2012-05
期刊：
影响因子：
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通讯作者：
Zhipeng Yu;D. Fan;B. Gui;Lei Shi;C. Xuan;L. Shan;Qian Wang;Y. Shang;Yan Wang
中科院分区：
文献类型：
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作者：
Zhipeng Yu;D. Fan;B. Gui;Lei Shi;C. Xuan;L. Shan;Qian Wang;Y. Shang;Yan Wang
背景：TDP-43是几种神经退行性疾病的主要病理标志。结果：TDP-43与FMRP/STAU1相互作用，结合SIRT1 mRNA的3′-UTR，促进其稳定性。结论：TDP-43、FMRP和STAU1形成一个功能协调的复合物，调控SIRT1的表达。意义：增加我们对TDP-43在神经退行性疾病中的机制作用的认识。尽管43 kDa的反应性dna结合蛋白（TDP-43）在许多神经退行性疾病中被鉴定为主要的病理标志蛋白，但TDP-43在神经退行性疾病中的机制作用仍然知之甚少。在这里，我们报道了TDP-43与脆性X智力迟钝蛋白（FMRP）和Staufen （STAU1）物理相关，形成一个功能复合物。差异微阵列分析显示，包括Sirtuin （SIRT1）在内的一系列功能重要基因的表达受该复合体的调节。RNA免疫沉淀（RIP）和RNA下拉实验表明，TDP-43/FMRP/STAU1特异性结合SIRT1 mRNA的3 ' -UTR，敲低这三种蛋白中的任何一种的表达都会导致SIRT1 mRNA和蛋白的减少。SIRT1参与双链DNA断裂修复，是细胞存活所必需的。事实上，TDP-43/FMRP/STAU1的缺失使细胞对凋亡和DNA损伤敏感。总之，我们的研究结果揭示了TDP-43细胞功能的分子机制，并可能为了解TDP-43在神经退行性疾病中的机制作用提供新的思路。
Background: TDP-43 is a major pathological hallmark of several neurodegenerative diseases. Results: TDP-43 interacts with FMRP/STAU1 and binds to the 3′-UTR of SIRT1 mRNA to promote its stability. Conclusion: TDP-43, FMRP, and STAU1 form a functionally coordinated complex to regulate the expression of SIRT1. Significance: Adding to our understanding of the mechanistic role of TDP-43 in neurodegenerative diseases. Despite the identification of the 43 kDa transactive response DNA-binding protein (TDP-43) as a major pathological signatory protein in a wide range of neurodegenerative diseases, the mechanistic role of TDP-43 in neurodegenerative disorders is still poorly understood. Here, we report that TDP-43 is physically associated with fragile X mental retardation protein (FMRP) and Staufen (STAU1) to form a functional complex. Differential microarray analysis revealed that the expression of a collection of functionally important genes including Sirtuin (SIRT1) is regulated by this complex. RNA-immunoprecipitation (RIP) and RNA pull-down assays demonstrated that TDP-43/FMRP/STAU1 specifically binds to the 3′-UTR of SIRT1 mRNA, and that knockdown the expression of any one of these three proteins resulted in the reduction of SIRT1 mRNA and protein. SIRT1 is implicated in double-stranded DNA break repair and is required for cell survival. Indeed, depletion of TDP-43/FMRP/STAU1 sensitizes cells to apoptosis and DNA damages. Collectively, our results revealed a molecular mechanism for the cellular function of TDP-43 and might shed new light on the understanding of the mechanistic role of TDP-43 in neurodegenerative diseases.