Lipopolysaccharide induces GFAT2 expression to promote O-Linked b-N-Acetylglucosaminylation and attenuate inflammation in macrophages

Hasanain Al-Mukh, Léa Baudoin, Abdelouhab Bouaboud, José Luis Sanchez-Salgado, Nabih Maraqa, Mostafa Khair, Patrick Pagesy, Georges Bismuth, Florence Niedergang, Tarik Issad

Research output: Contribution to journalArticlepeer-review

Abstract

Glycosylation with O-linked b-N-acetylglucosamine (O-GlcNAcylation) is a reversible posttranslational modification that regulates the activity of intracellular proteins according to glucose availability and its metabolism through the hexosamine biosynthesis pathway. This modification has been involved in the regulation of various immune cell types, including macrophages. However, little is known concerning the mechanisms that regulate the protein O-GlcNAcylation level in these cells. In the present work, we demonstrate that LPS treatment induces a marked increase in protein O-GlcNAcylation in RAW264.7 cells, bone marrow–derived and peritoneal mouse macrophages, as well as human monocyte-derived macrophages. Targeted deletion of OGT in macrophages resulted in an increased effect of LPS on NOS2 expression and cytokine production, suggesting that O-GlcNAcylation may restrain inflammatory processes induced by LPS. The effect of LPS on protein O-GlcNAcylation in macrophages was associated with an increased expression and activity of glutamine fructose 6-phosphate amidotransferase (GFAT), the enzyme that catalyzes the rate-limiting step of the hexosamine biosynthesis pathway. More specifically, we observed that LPS potently stimulated GFAT2 isoform mRNA and protein expression. Genetic or pharmacological inhibition of FoxO1 impaired the LPS effect on GFAT2 expression, suggesting a FoxO1-dependent mechanism. We conclude that GFAT2 should be considered a new LPS-inducible gene involved in regulation of protein O-GlcNAcylation, which permits limited exacerbation of inflammation upon macrophage activation.

Original languageEnglish (US)
Pages (from-to)2499-2510
Number of pages12
JournalJournal of Immunology
Volume205
Issue number9
DOIs
StatePublished - Nov 1 2020

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint

Dive into the research topics of 'Lipopolysaccharide induces GFAT2 expression to promote O-Linked b-N-Acetylglucosaminylation and attenuate inflammation in macrophages'. Together they form a unique fingerprint.

Cite this