Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine.
Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine.
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受损的eIF5A功能导致孟德尔疾病，其在模型系统中被亚精胺部分挽救。
DOI：
10.1038/s41467-021-21053-2
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发表时间：
2021-02-05
影响因子：
16.6
通讯作者：
Banka S
中科院分区：
文献类型：
--
作者：
Faundes V;Jennings MD;Crilly S;Legraie S;Withers SE;Cuvertino S;Davies SJ;Douglas AGL;Fry AE;Harrison V;Amiel J;Lehalle D;Newman WG;Newkirk P;Ranells J;Splitt M;Cross LA;Saunders CJ;Sullivan BR;Granadillo JL;Gordon CT;Kasher PR;Pavitt GD;Banka S
脯氨酸的结构阻止了它采用快速蛋白质合成的最佳位置。高度保守的eIF5A可以解决与多聚脯氨酸链(PPT)相关的核糖体停滞问题，eIF5A是唯一一种含有亚精氨酸的蛋白质。我们发现新发现的EIF5A杂合变异导致一种以发育迟缓、小头畸形、小颌畸形和畸形的不同组合为特征的疾病。酵母生长分析、多聚体图谱、总eIF5A水平和PPT-Reports研究表明，这些突变体削弱了eIF5A的功能，减少了eIF5A与核糖体的相互作用，并损害了含有PPT的蛋白质的合成。添加1 mM亚精胺部分纠正了酵母生长缺陷，改善了多聚体图谱，并恢复了PPT报告基因的表达。在斑马鱼中，敲除eif5a基因部分概括了补充1 微米亚精胺可以挽救的人类表型。总之，我们揭示了eIF5A在人类发育和疾病中的作用，展示了EIF5A相关疾病的机制复杂性，并提出了其治疗的可能性。EIF5A对蛋白质合成至关重要，但尚未与先天性人类疾病有关。在这里，作者表明，EIF5A变体通过减少eIF5A与核糖体的相互作用而导致孟德尔紊乱，这种表型可以通过在酵母和斑马鱼中补充亚精胺来部分纠正。
The structure of proline prevents it from adopting an optimal position for rapid protein synthesis. Poly-proline-tract (PPT) associated ribosomal stalling is resolved by highly conserved eIF5A, the only protein to contain the amino acid hypusine. We show that de novo heterozygous EIF5A variants cause a disorder characterized by variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism. Yeast growth assays, polysome profiling, total/hypusinated eIF5A levels and PPT-reporters studies reveal that the variants impair eIF5A function, reduce eIF5A-ribosome interactions and impair the synthesis of PPT-containing proteins. Supplementation with 1 mM spermidine partially corrects the yeast growth defects, improves the polysome profiles and restores expression of PPT reporters. In zebrafish, knockdown eif5a partly recapitulates the human phenotype that can be rescued with 1 µM spermidine supplementation. In summary, we uncover the role of eIF5A in human development and disease, demonstrate the mechanistic complexity of EIF5A-related disorder and raise possibilities for its treatment. eIF5A is critical for protein synthesis but has not yet been associated with congenital human disease. Here, the authors show that EIF5A variants cause a Mendelian disorder via reduced eIF5A-ribosome interactions and this phenotype is partially corrected by spermidine supplementation in yeast and zebrafish.
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影响因子：
64.8
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