Deoxyhypusine synthase promotes a pro-inflammatory macrophage phenotype

Cell Metab. 2021 Sep 7;33(9):1883-1893.e7. doi: 10.1016/j.cmet.2021.08.003.

Abstract

The metabolic inflammation (meta-inflammation) of obesity is characterized by proinflammatory macrophage infiltration into adipose tissue. Catalysis by deoxyhypusine synthase (DHPS) modifies the translation factor eIF5A to generate a hypusine (Hyp) residue. Hypusinated eIF5A (eIF5AHyp) controls the translation of mRNAs involved in inflammation, but its role in meta-inflammation has not been elucidated. Levels of eIF5AHyp were found to be increased in adipose tissue macrophages from obese mice and in murine macrophages activated to a proinflammatory M1-like state. Global proteomics and transcriptomics revealed that DHPS deficiency in macrophages altered the abundance of proteins involved in NF-κB signaling, likely through translational control of their respective mRNAs. DHPS deficiency in myeloid cells of obese mice suppressed M1 macrophage accumulation in adipose tissue and improved glucose tolerance. These findings indicate that DHPS promotes the post-transcriptional regulation of a subset of mRNAs governing inflammation and chemotaxis in macrophages and contributes to a proinflammatory M1-like phenotype.

Keywords: diabetes; hypusine; inflammation; mRNA translation; macrophage; obesity; polyamines; proteomics; transcriptomics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / metabolism
  • Animals
  • Inflammation / metabolism
  • Macrophages / metabolism
  • Mice
  • Oxidoreductases Acting on CH-NH Group Donors* / chemistry
  • Oxidoreductases Acting on CH-NH Group Donors* / genetics
  • Oxidoreductases Acting on CH-NH Group Donors* / metabolism
  • Phenotype

Substances

  • Oxidoreductases Acting on CH-NH Group Donors
  • deoxyhypusine synthase