Deoxyhypusine synthase, an essential enzyme for hypusine biosynthesis, is required for proper exocrine pancreas development

Abstract

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Neuron-specific ablation of eIF5A or deoxyhypusine synthase leads to impairments in growth, viability, neurodevelopment, and cognitive functions in mice

“…For PCR analysis, mouse tail DNA was amplified using JumpStart Taq ReadyMix (Millipore Sigma). The Dhps lox PCR and Eif5a lox PCR reactions were carried out as described previously (7,8).…”

“…More recently, germ line, de novo, heterozygous EIF5A variants were also reported to be associated with a neurodevelopmental disorder (27) Emx1-Cre mediated knockout of Eif5a or Dhps was achieved by two-step breeding. First, Eif5a fl/fl (8) or Dhps fl/fl (7) mouse was mated with Emx1-IRES-Cre mouse (30) to generate either Eif5a fl/+ ;Emx1-Cre or Dhps fl/+ ;Emx1-Cre mouse, which was mated again with mice carrying their respective homozygous floxed allele to produce either Eif5a fl/fl ; Emx1-Cre or Dhps fl/fl ;Emx1-Cre mice. Camk2a-Cre mediated knockout of Eif5a or Dhps was achieved as above by the two-step breeding, using the Camk2a-Cre transgenic strain T29-1 (31).…”

“…1 ). Homozygous, whole-body deletion of any of these three genes, Eif5a , Dhps , or Dohh , in mice causes early embryonic lethality ( 5 , 6 ), and postnatal conditional deletion of Eif5a or Dhps leads to inhibition of organ development in mice ( 7 , 8 ).

Figure 1 The pathways of polyamine biosynthesis and hypusine modification in eIF5A.

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Deoxyhypusine synthase promotes a pro-inflammatory macrophage phenotype

“…The hypusine modification is critical for eIF5A function and is catalyzed by the sequential action of two enzymes: deoxyhypusine synthase (DHPS) for transfer of a 4-aminobutyl moiety of the polyamine spermidine to Lys50 residue of eIF5A and deoxyhypusine hydroxylase (DOHH) for hydroxylation of the deoxyhypusine residue (Park et al, 2010). EIF5A Hyp functions in mRNA translation during cellular processes that include proliferation, apoptosis, and cell differentiation (Gregio et al, 2009;Levasseur et al, 2019;Padgett et al, 2021;Robbins et al, 2010;Saini et al, 2009;Schuller et al, 2017). A role for eIF5A Hyp has also been implicated in the translation of mRNAs involved in inflammation (de Almeida et al, 2014;Gobert et al, 2020;Maier et al, 2010).…”

“…Although Immune cells from the adipose stromal vascular fraction (SVF) were isolated from male C57BL6/J mice (n = 10 per group) fed a low-fat diet (LFD, 10% kcal from fat) or a high-fat diet (HFD, 60% kcal from fat) for 16 weeks and samples were analyzed by flow cytometry using specific antibodies, immunoblotting, or polyribosome profiling. (A and B) Quantification of CD45+ cells (A) and CD45+ eIF5A Hyp global Dhps gene disruption generates an embryonic-lethal phenotype in mice (Nishimura et al, 2012), the physiological roles of eIF5A Hyp have been investigated by utilizing pharmacologic inhibitors of DHPS in mice and cell lines and conditional knockout mice (Colvin et al, 2013;Gobert et al, 2020;Levasseur et al, 2019;Maier et al, 2010;Padgett et al, 2021;Puleston et al, 2019). However, to date, assessment of the role of DHPS in macrophages in vivo in the setting of meta-inflammation has not been undertaken.…”