Eukaryotic translation initiation factor 5A and its posttranslational modifications play an important role in proliferation and potentially in differentiation of the human enteric protozoan parasite Entamoeba histolytica

Abstract

The eukaryotic translation initiation factor 5A (eIF5A) is a highly conserved protein and is essential in all eukaryotes. However, the specific roles of eIF5A in translation and in other biological processes remain elusive. In the present study, we described the role of eIF5A, its posttranslational modifications (PTM), and the biosynthetic pathway needed for the PTM in Entamoeba histolytica, the protozoan parasite responsible for amoebic dysentery and liver abscess in humans. E. histolytica encodes two isotypes of eIF5A and two isotypes of enzymes, deoxyhypusine synthase (DHS), responsible for their PTM. Both of the two eIF5A isotypes are functional, whereas only one DHS (EhDHS1, but not EhDHS2), is catalytically active. The DHS activity increased ~2000-fold when EhDHS1 was co-expressed with EhDHS2 in Escherichia coli, suggesting that the formation of a heteromeric complex is needed for full enzymatic activity. Both EhDHS1 and 2 genes were required for in vitro growth of E. histolytica trophozoites, indicated by small antisense RNA-mediated gene silencing. In trophozoites, only eIF5A2, but not eIF5A1, gene was actively transcribed. Gene silencing of eIF5A2 caused compensatory induction of expression of eIF5A1 gene, suggesting interchangeable role of the two eIF5A isotypes and also reinforcing the importance of eIF5As for parasite proliferation and survival. Furthermore, using a sibling species, Entamoeba invadens, we found that eIF5A1 gene was upregulated during excystation, while eIF5A2 was downregulated, suggesting that eIF5A1 gene plays an important role during differentiation. Taken together, these results have underscored the essentiality of eIF5A and DHS, for proliferation and potentially in the differentiation of this parasite, and suggest that the hypusination associated pathway represents a novel rational target for drug development against amebiasis.

Diabetology: Feature Papers 2021

“…Deoxyhypusine synthase (DHPS)-driven eIF5A hypusination was recently shown to be a feature of proinflammatory macrophages, and DHPS deletion in macrophages resulted in improved insulin sensitivity and glucose homeostasis. Furthermore, hypusination is being increasingly implicated in metabolic diseases and microbial infections [213,214], hypusine polyamine precursors have been reported in intestinal epithelial renewal and M2 macrophage polarization [215], and dietary spermidine was recently shown to boost eIF5A hypusination and protect mitochondrial dysfunction during brain aging [216]. The polyamine pathway intermediate spermidine was recently reported to induce anti-inflammatory pathways following release from apoptotic cells [217]; it has protective effects in metabolic diseases and has emerged as a well-tolerable caloric restriction mimetic and provider of nitric oxide and arginine bioavailability [218].…”

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

“…Since eIF5A is highly conserved and is essential to all eukaryotes it may represent a new option for a pharmacological targeting of various diseases due to eukaryotic pathogens. A recent study by Jeelani and Nozaki [ 107 ] reported that eIF5A and its post-translational modification is essential for both proliferation and differentiation of Entamoeba histolytica , the protozoan responsible for amoebic dysentery and liver abscess in humans. They showed that Entamoeba eIF5A is involved in excystation, conversion from the cyst to the trophozoite, but not in encystation.…”