Universität zu Köln

Williams, Niamh C., Ryan, Dylan G., Costa, Ana S. H., Mills, Evanna L., Jedrychowski, Mark P., Cloonan, Suzanne M., Frezza, Christian and O'Neill, Luke A. (2022). Signaling metabolite L-2-hydroxyglutarate activates the transcription factor HIF-1 alpha in lipopolysaccharide-activated macrophages. J. Biol. Chem., 298 (2). AMSTERDAM: ELSEVIER. ISSN 1083-351X

Full text not available from this repository.

Abstract

Activated macrophages undergo metabolic reprogram-ming, which not only supports their energetic demands but also allows for the production of specific metabolites that function as signaling molecules. Several Krebs cycles, or Krebs-cycle-derived metabolites, including succinate, alpha- ketoglutarate, and itaconate, have recently been shown to modulate macrophage function. The accumulation of 2-hydroxyglutarate (2HG) has also been well documented in transformed cells and more recently shown to play a role in T cell and dendritic cell function. Here we have found that the abundance of both enantiomers of 2HG is increased in LPS-activated macrophages. We show that L-2HG, but not D-2HG, can promote the expression of the proinflammatory cytokine IL-1 beta and the adoption of an inflammatory, highly glycolytic metabolic state. These changes are likely mediated through activation of the transcription factor hypoxia-inducible factor-1 alpha (HIF-1 alpha) by L-2HG, a known inhibitor of the HIF prolyl hydroxylases. Expression of the enzyme responsible for L-2HG degradation, L-2HG dehydrogenase (L-2HGDH), was also found to be decreased in LPS-stimulated macrophages and may therefore also contribute to L-2HG accumulation. Finally, overexpression of L-2HGDH in HEK293 TLR4/MD2/CD14 cells inhibited HIF-1 alpha activa-tion by LPS, while knockdown of L-2HGDH in macrophages boosted the induction of HIF-1 alpha-dependent genes, as well as increasing LPS-induced HIF-1 alpha activity. Taken together, this study therefore identifies L-2HG as a metabolite that can regulate HIF-1 alpha in macrophages.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Williams, Niamh C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ryan, Dylan G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Costa, Ana S. H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mills, Evanna L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jedrychowski, Mark P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cloonan, Suzanne M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Frezza, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED O'Neill, Luke A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-689931
DOI:	10.1016/j.jbc.2021.101501
Journal or Publication Title:	J. Biol. Chem.
Volume:	298
Number:	2
Date:	2022
Publisher:	ELSEVIER
Place of Publication:	AMSTERDAM
ISSN:	1083-351X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ONCOMETABOLITE 2-HYDROXYGLUTARATE; PROTEIN-PHOSPHORYLATION; CELL; SUCCINATE; CANCER Multiple languages Biochemistry & Molecular Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68993