The eukaryotic initiation factor 5A (eIF5A1), the molecule, mechanisms and recent insights into the pathophysiological roles

Abstract

Since the demonstration of its involvement in cell proliferation, the eukaryotic initiation factor 5A (eIF5A) has been studied principally in relation to the development and progression of cancers in which the isoform A2 is mainly expressed. However, an increasing number of studies report that the isoform A1, which is ubiquitously expressed in normal cells, exhibits novel molecular features that reveal its new relationships between cellular functions and organ homeostasis. At a first glance, eIF5A can be regarded, among other things, as a factor implicated in the initiation of translation. Nevertheless, at least three specificities: (1) its extreme conservation between species, including plants, throughout evolution, (2) its very special and unique post-translational modification through the activating-hypusination process, and finally (3) its close relationship with the polyamine pathway, suggest that the role of eIF5A in living beings remains to be uncovered. In fact, and beyond its involvement in facilitating the translation of proteins containing polyproline residues, eIF5A is implicated in various physiological processes including ischemic tolerance, metabolic adaptation, aging, development, and immune cell differentiation. These newly discovered physiological properties open up huge opportunities in the clinic for pathologies such as, for example, the ones in which the oxygen supply is disrupted. In this latter case, organ transplantation, myocardial infarction or stroke are concerned, and the current literature defines eIF5A as a new drug target with a high level of potential benefit for patients with these diseases or injuries. Moreover, the recent use of genomic and transcriptomic association along with metadata studies also revealed the implication of eIF5A in genetic diseases. Thus, this review provides an overview of eIF5A from its molecular mechanism of action to its physiological roles and the clinical possibilities that have been recently reported in the literature.

Arginine-dependent hypusination of the eukaryotic translation initiation factor (eIF)5A drives erythroid lineage differentiation

“…Translation is a critical component in the regulation of multiple developmental pathways, cell activation, and cancer progression (Fabbri et al, 2021; Sanchez et al, 2016; Sonenberg and Hinnebusch, 2007; Tahmasebi et al, 2018). Within the broad realm of protein synthesis, hypusinated eIF5A while stimulating general translation, also drives specific translational programs impacting cancer, diabetes, and infectious diseases (Dever et al, 2014; Hoque et al, 2017; Kaiser, 2012; Tauc et al, 2021). Notably though the impact of eIF5A in erythropoiesis, a process that is particularly sensitive to translational regulation, has not been evaluated.…”

“…Notably, it is the only protein in eukaryotes and archaea to contain the amino acid hypusine [ N ε -(4-amino-2-hydroxybutyl)lysine], a modification that is essential for its activity (Park and Wolff, 2018; Saini et al, 2009; Wolff et al, 2007). eIF5A is required for the growth of S. cerevisiae (Chattopadhyay et al, 2008) and has also been shown to be highly expressed at all mouse embryonic stages, with hypusination required for muscle differentiation (Parreiras-e-Silva et al, 2010; Tauc et al, 2021). Moreover, in humans, heterozygous variants in EIF5A have recently been shown to cause a syndrome characterized by developmental delay, microcephaly, and congenital malformations (Faundes et al, 2021).…”

Initiation and elongation factor co-expression correlates with recurrence and survival in epithelial ovarian cancer

“…eIF5A has been reported to be the only protein containing hypusine and the subunit is activated by post-translational synthesis of hypusine [ 48 ]. It has been proposed that hypusinated eIF5A is a RNA binding protein associated with exportins [ 49 ]. Interestingly hypusinated eIF5A, which impacts protein synthesis was shown to be mainly localized in the cytoplasm [ 48 ].…”

Ribotoxic collisions on CAG expansions disrupt proteostasis and stress responses in Huntington’s Disease

“…By facilitating translation elongation on ribosome pause sites e.g. PPX, eIF5A supports protein and organelle biogenesis, autophagy and immune functions 43 —all of which are key cellular pathways often deregulated in HD 1,3 . eIF5A is also involved in the regulation of key enzymes mediating polyamine metabolism 44 .…”