Anderson Cara M, Kulkarni Abhishek, Maier Bernhard, Huang Fei, Figatner Kayla, Chakraborty Advaita, Pratuangtham Sarida, May Sarah C, Tersey Sarah A, Anderson Ryan M, Mirmira Raghavendra G
Kovler Diabetes Center, The University of Chicago, Chicago, Illinois, USA; Biological Sciences Division, The University of Chicago, Chicago, Illinois, USA.
Kovler Diabetes Center, The University of Chicago, Chicago, Illinois, USA.
J Biol Chem. 2025 Feb;301(2):108209. doi: 10.1016/j.jbc.2025.108209. Epub 2025 Jan 18.
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) in cellular proliferation is well characterized, the role of its unhypusinated form (eIF5A) remains unclear. We hypothesized that eIF5A exerts independent and negative effects on cellular replication and metabolism, distinct from the loss of eIF5A. 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. 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 in regulating developmental and functional responses in pancreas health and disease.
真核生物翻译起始因子5A（eIF5A）的hypusination修饰对于其在翻译延伸和终止中的作用至关重要。尽管hypusinated形式的eIF5A（eIF5A）在细胞增殖中的功能已得到充分表征，但其未被hypusinated修饰的形式（eIF5A）的作用仍不清楚。我们假设eIF5A对细胞复制和代谢发挥独立的负面影响，这与eIF5A缺失的影响不同。为了验证这一假设，我们利用斑马鱼和小鼠模型，通过诱导敲低脱氧hypusine合酶（DHPS）和eIF5A来研究它们在细胞生长中的作用。通过RNA测序进行基因表达分析，并对胰腺和β细胞质量进行形态测量，以评估表型变化并确定受影响的生物学途径。斑马鱼中DHPS的缺失导致胰腺生长出现明显缺陷，同时伴有与mRNA翻译、神经发生和应激途径相关的基因表达变化。相比之下，敲低eIF5A对胰腺发育的影响最小，这表明DHPS缺失的影响并非仅仅是由于缺乏eIF5A。在小鼠中，β细胞特异性缺失DHPS会损害β细胞质量的扩展和葡萄糖耐受性，而eIF5A的缺失则没有统计学上的显著影响。这些发现为eIF5A在调节胰腺健康和疾病中的发育和功能反应方面的独立作用提供了证据。
