Hypusination Orchestrates the Antimicrobial Response of Macrophages

Alain P Gobert,Jordan L Finley,Yvonne L Latour,Mohammad Asim,Thaddeus M Smith,Thomas G Verriere,Daniel P Barry,Margaret M Allaman,Alberto G Delagado,Kristie L Rose,M Wade Calcutt,Kevin L Schey,Johanna C Sierra,M Blanca Piazuelo,Raghavendra G Mirmira,Keith T Wilson

doi:10.1016/j.celrep.2020.108510

Abstract

SUMMARYInnate responses of myeloid cells defend against pathogenic bacteria via inducible effectors. Deoxyhypusine synthase (DHPS) catalyzes the transfer of the N-moiety of spermidine to the lysine-50 residue of eukaryotic translation initiation factor 5A (EIF5A) to form the amino acid hypusine. Hypusinated EIF5A (EIF5AHyp) transports specific mRNAs to ribosomes for translation. We show that DHPS is induced in macrophages by two gastrointestinal pathogens, Helicobacter pylori and Citrobacter rodentium, resulting in enhanced hypusination of EIF5A. EIF5AHyp was also increased in gastric macrophages from patients with H. pylori gastritis. Furthermore, we identify the bacteria-induced immune effectors regulated by hypusination. This set of proteins includes essential constituents of antimicrobial response and autophagy. Mice with myeloid cell-specific deletion of Dhps exhibit reduced EIF5AHyp in macrophages and increased bacterial burden and inflammation. Thus, regulation of translation through hypusination is a critical hallmark of the defense of eukaryotic hosts against pathogenic bacteria.

Highlights

The mammalian gastrointestinal tract is the home of the largest population of myeloid cells (Lee et al, 1985)
In response to this pathogen, bone-marrowderived macrophages (BMmacs) from Dhpsfl/fl mice exhibited a significant increase in Dhps mRNA expression, whereas the Dohh level was not affected by the infection (Figure 1B)
This induction was reduced by blocking phosphatidylinositol 3-kinase (PI3K) with LY294002 (Figures S1A and S1B); inhibitors of nuclear factor κB (NF-κB), mitogen-activated protein kinase 14 (MAPK14), MAPK1/3, or MAP2K1 had no effect on H. pylori-induced Deoxyhypusine synthase (DHPS) protein expression (Figures S1A and S1B), indicating that signaling through PI3K is involved in stimulation of DHPS in infected macrophages

Summary

Introduction

The mammalian gastrointestinal tract is the home of the largest population of myeloid cells (Lee et al, 1985) These resident and infiltrating cells respond to inflammatory signals and to foreign antigens, exhibiting enhanced antimicrobial abilities that are needed for the clearance of pathogens (Hardbower et al, 2017; Niess et al, 2005; Wennerås et al, 2000). Using mice with myeloid-specific Odc knockout, we found that endogenous putrescine alters histone methylation/acetylation and dampens the transcription of the genes encoding proinflammatory markers (Hardbower et al, 2017) This results in the limitation of inflammation and the exacerbation of H. pylori burden (Hardbower et al, 2017). The importance of spermidine for the outcome of the infection remains unknown

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