PDF(Pubmed)
Abstract：
The unique amino acid hypusine [Nε-(4-amino-2-hydroxybutyl)lysine] is exclusively formed on the translational regulator eukaryotic initiation factor 5A (eIF5A) via a process coined hypusination. Hypusination is mediated by two enzymes, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH), and hypusinated eIF5A (eIF5AHyp) promotes translation elongation by alleviating ribosome pauses at amino acid motifs that cause structural constraints, and it also facilitates translation initiation and termination. Accordingly, eIF5AHyp has diverse biological functions that rely on translational control of its targets. Homozygous deletion of Eif5a, Dhps, or Dohh in mice leads to embryonic lethality, and heterozygous germline variants in EIF5A and biallelic variants in DHPS and DOHH are associated with rare inherited neurodevelopmental disorders, underscoring the importance of the hypusine circuit for embryonic and neuronal development. Given the pleiotropic effects of eIF5AHyp, a detailed understanding of the cell context-specific intrinsic roles of eIF5AHyp and of the chronic versus acute effects of eIF5AHyp inhibition is necessary to develop future strategies for eIF5AHyp-targeted therapy to treat various human health problems. Here, we review the most recent studies documenting the intrinsic roles of eIF5AHyp in different tissues/cell types under normal or pathophysiological conditions and discuss these unique aspects of eIF5AHyp-dependent translational control.
摘要：
独特的氨基酸hypusine[Nε-（4-氨基-2-羟丁基）赖氨酸]仅通过一个过程在翻译调节因子真核起始因子5A（eIF5A）上形成。催眠是由两种酶介导的，脱氧羟酶合酶（DHPS）和脱氧羟酶（DOHH），和低活性的eIF5A（eIF5AHyp）通过减轻氨基酸基序的核糖体停顿来促进翻译延伸，从而导致结构约束，它还有助于翻译的启动和终止。因此，eIF5AHyp具有依赖于其靶标的翻译控制的多种生物学功能。Eif5a的纯合缺失，Dhps,或Dohh在小鼠中导致胚胎致死，EIF5A中的杂合种系变异体和DHPS和DOHH中的双等位基因变异体与罕见的遗传性神经发育障碍有关，强调hypusine回路对胚胎和神经元发育的重要性。鉴于eIF5AHyp的多效性，详细了解eIF5AHyp的细胞环境特异性内在作用以及eIF5AHyp抑制的慢性和急性效应对于制定eIF5AHyp靶向治疗治疗各种人类健康问题的未来策略是必要的。这里,我们回顾了最近的研究，这些研究记录了在正常或病理生理条件下，eIF5AHyp在不同组织/细胞类型中的内在作用，并讨论了eIF5AHyp依赖性翻译控制的这些独特方面。
