Hypusinated and unhypusinated isoforms of the translation factor eIF5A exert distinct effects in models of pancreas...

Hypusination of eukaryotic translation initiation factor 5A (eIF5A) is essential for its role in translation elongation and termination. Although the function of hypusinated eIF5A (eIF5A^Hyp) in cellular proliferation is well characterized, the role of its unhypusinated form (eIF5A^Lys) remains unclear. We hypothesized that eIF5A^Lys exerts independent and negative effects on cellular replication and metabolism, distinct from the loss of eIF5A^Hyp. To test this hypothesis, we utilized zebrafish and mouse models with inducible knockdowns of deoxyhypusine synthase (DHPS) and eIF5A to investigate their roles in cellular growth. Gene expression analysis via RNA sequencing and morphometric measurements of pancreas and β-cell mass were performed to assess phenotypic changes and identify affected biological pathways. Loss of DHPS in zebrafish resulted in significant defects in pancreatic growth, accompanied by changes in gene expression related to mRNA translation, neurogenesis, and stress pathways. By contrast, knockdown of eIF5A had minimal impact on pancreas development, suggesting that the effects of DHPS loss are not solely because of the lack of eIF5A^Hyp. In mice, β-cell-specific deletion of DHPS impaired β-cell mass expansion and glucose tolerance, whereas eIF5A deletion had no statistically significant effects. These findings provide evidence for an independent role for eIF5A^Lys in regulating developmental and functional responses in pancreas health and disease.