Biochemical and genetic evidence for a role of IGHMBP2 in the translational machinery
Biochemical and genetic evidence for a role of IGHMBP2 in the translational machinery
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DOI：
10.1093/hmg/ddp134
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发表时间：
2009-06-15
影响因子：
3.5
通讯作者：
Mourelatos, Zissimos
中科院分区：
文献类型：
--
作者：
de Planell-Saguer, Mariangels;Schroeder, David G.;Mourelatos, Zissimos
人类运动神经元退行性疾病 1 型呼吸窘迫脊髓性肌萎缩症 (SMARD1) 是由免疫球蛋白 mu 结合蛋白 2 (IGHMBP2) 的功能缺失突变引起的，IGHMBP2 是一种功能未知的蛋白质，含有 DNA/RNA 解旋酶和核酸结合域。神经肌肉变性 (nmd) 小鼠（SMARD1 的小鼠模型）中 IGHMBP2 蛋白水平降低会导致运动神经元变性。我们报告了 IGHMBP2 的生化特征以及拯救 nmd 小鼠表型和运动神经元变性的修饰基因座的分离。我们发现源自 CAST/EiJ 小鼠的 166 kb BAC 转基因含有 tRNA 基因和基础转录激活剂 1 (Abt1)（一种核糖体生物发生所需的蛋白质编码基因），含有负责运动神经元救援的遗传修饰剂。我们的生化研究表明，IGHMBP2 与 tRNA，特别是与修饰剂中存在的 tRNA(Tyr) 以及 ABT1 蛋白存在物理关联。我们发现转录因子 IIIC-220 kDa (TFIIIC220)（tRNA 转录所需的必需因子）以及解旋酶 Reptin 和 Pontin（在转录和核糖体生物合成中发挥作用）也是包含 IGHMBP2 的复合物的一部分。我们的研究结果强烈表明 IGHMBP2 是翻译机制的一个组成部分，并且这些组成部分可以通过基因操作来抑制运动神经元变性。
The human motor neuron degenerative disease spinal muscular atrophy with respiratory distress type 1 (SMARD1) is caused by loss of function mutations of immunoglobulin mu-binding protein 2 (IGHMBP2), a protein of unknown function that contains DNA/RNA helicase and nucleic acid-binding domains. Reduced IGHMBP2 protein levels in neuromuscular degeneration (nmd) mice, the mouse model of SMARD1, lead to motor neuron degeneration. We report the biochemical characterization of IGHMBP2 and the isolation of a modifier locus that rescues the phenotype and motor neuron degeneration of nmd mice. We find that a 166 kb BAC transgene derived from CAST/EiJ mice and containing tRNA genes and activator of basal transcription 1 (Abt1), a protein-coding gene that is required for ribosome biogenesis, contains the genetic modifier responsible for motor neuron rescue. Our biochemical investigations show that IGHMBP2 associates physically with tRNAs and in particular with tRNA(Tyr), which are present in the modifier and with the ABT1 protein. We find that transcription factor IIIC-220 kDa (TFIIIC220), an essential factor required for tRNA transcription, and the helicases Reptin and Pontin, which function in transcription and in ribosome biogenesis, are also part of IGHMBP2-containing complexes. Our findings strongly suggest that IGHMBP2 is a component of the translational machinery and that these components can be manipulated genetically to suppress motor neuron degeneration.