Dataset Information

Human AlkB homologue 5 is a nuclear 2-oxoglutarate dependent oxygenase and a direct target of hypoxia-inducible factor 1? (HIF-1?).

ABSTRACT: Human 2-oxoglutarate oxygenases catalyse a range of biological oxidations including the demethylation of histone and nucleic acid substrates and the hydroxylation of proteins and small molecules. Some of these processes are centrally involved in regulation of cellular responses to hypoxia. The ALKBH proteins are a sub-family of 2OG oxygenases that are defined by homology to the Escherichia coli DNA-methylation repair enzyme AlkB. Here we report evidence that ALKBH5 is probably unique amongst the ALKBH genes in being a direct transcriptional target of hypoxia inducible factor-1 (HIF-1) and is induced by hypoxia in a range of cell types. We show that purified recombinant ALKBH5 is a bona fide 2OG oxygenase that catalyses the decarboxylation of 2OG but appears to have different prime substrate requirements from those so far defined for other ALKBH family members. Our findings define a new class of HIF-transcriptional target gene and suggest that ALKBH5 may have a role in the regulation of cellular responses to hypoxia.

SUBMITTER: Thalhammer A

PROVIDER: S-EPMC3021549 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Human AlkB homologue 5 is a nuclear 2-oxoglutarate dependent oxygenase and a direct target of hypoxia-inducible factor 1α (HIF-1α).

Thalhammer Armin A Bencokova Zuzana Z Poole Rachel R Loenarz Christoph C Adam Julie J O'Flaherty Linda L Schödel Johannes J Mole David D Giaslakiotis Konstantinos K Schofield Christopher J CJ Hammond Ester M EM Ratcliffe Peter J PJ Pollard Patrick J PJ

PloS one 20110114 1

Human 2-oxoglutarate oxygenases catalyse a range of biological oxidations including the demethylation of histone and nucleic acid substrates and the hydroxylation of proteins and small molecules. Some of these processes are centrally involved in regulation of cellular responses to hypoxia. The ALKBH proteins are a sub-family of 2OG oxygenases that are defined by homology to the Escherichia coli DNA-methylation repair enzyme AlkB. Here we report evidence that ALKBH5 is probably unique amongst the ...[more]

PMID: 21264265

Similar Datasets

Project description:Neutrophil extracellular traps (NETs) immobilize pathogens during early stages of systemic inflammation but as the reaction progresses they become detrimental to endothelial cells and the organ-specific cells. For this reason it would be of importance to control their formation by either physiological or pharmacological means. Endogenously, formation of NETs is under control of cellular and whole organism metabolism as shown previously in the course of bacterial systemic inflammation, obesity or the combination of the two. Numerous leukocytes are subjected to immunometabolic regulation and in macrophages exposure to lipopolysaccharide (LPS) leads to two breaks in the Krebs cycle that impact this cell functioning. As a consequence of the first break, anti-microbial itaconic acid (itaconate) is produced whereas the second break activates hypoxia-inducible factor-1α (Hif-1α). In turn, itaconate activates transcription of the anti-inflammatory nuclear factor erythroid 2-related factor 2 (Nrf2) which upregulates cyto-protective heme oxygenase (HO-1). Here we report that exogenously added derivative of the itaconic acid, 4-octyl itaconate (4-OI), diminishes formation of NETs by neutrophils of either normal (lean) or obese mice, and independently of the age of the animals or immunoaging. Elucidating the mechanism of this inhibition we unravel that although Nrf2/HO-1 expression itself is not altered by 4-OI, it is up-regulated when compared against the NET formation while Hif-1α is downregulated in 4-OI-pre-treated LPS-stimulated neutrophils in either way. We further show that blockage of Hif-1α by its specific inhibitor diminishes NET release as does inhibition by 4-OI. Also inhibition of HO-1 activity correlates with diminished LPS-induced NET release upon pre-treatment with 4-OI albeit LPS alone induced NETs are not HO-1-dependent. In summary, we unravel that 4-OI inhibits NET formation by murine neutrophils independently of their origin (health vs. metabolically challenged animals) and the age of individuals/immunosenescence via inhibition of Hif-1α and induction of HO-1.

Dataset Information

Human AlkB homologue 5 is a nuclear 2-oxoglutarate dependent oxygenase and a direct target of hypoxia-inducible factor 1? (HIF-1?).

Publications

Human AlkB homologue 5 is a nuclear 2-oxoglutarate dependent oxygenase and a direct target of hypoxia-inducible factor 1α (HIF-1α).

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets