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Cell Rep. 2015 Dec 15;13(10):2048-55. doi: 10.1016/j.celrep.2015.11.005. Epub 2015 Nov 25.

Ferritin-Mediated Iron Sequestration Stabilizes Hypoxia-Inducible Factor-1α upon LPS Activation in the Presence of Ample Oxygen.

Author information

1
Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany.
2
Department of Nephrology and Hypertension, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU), 91054 Erlangen, Germany.
3
Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
4
Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg, 93053 Regensburg, Germany.
5
Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany.
6
Heisenberg Research Group, Department of Clinical Pathobiochemistry, Institute of Clinical Chemistry and Laboratory Medicine, University of Technology, 01307 Dresden, Germany.
7
Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University Göttingen, 37073 Göttingen, Germany.
8
Department of Chemistry and Pharmacy, Inorganic Chemistry, Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, 91058 Erlangen, Germany.
9
Department of Internal Medicine I, University of Regensburg, 93053 Regensburg, Germany.
10
Division of Virus-Associated Carcinogenesis, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
11
European Molecular Biology Laboratory, 69120 Heidelberg, Germany.
12
Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, 90014 Oulu, Finland.
13
Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany; Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg, 93053 Regensburg, Germany. Electronic address: jonathan.jantsch@ukr.de.

Abstract

Both hypoxic and inflammatory conditions activate transcription factors such as hypoxia-inducible factor (HIF)-1α and nuclear factor (NF)-κB, which play a crucial role in adaptive responses to these challenges. In dendritic cells (DC), lipopolysaccharide (LPS)-induced HIF1α accumulation requires NF-κB signaling and promotes inflammatory DC function. The mechanisms that drive LPS-induced HIF1α accumulation under normoxia are unclear. Here, we demonstrate that LPS inhibits prolyl hydroxylase domain enzyme (PHD) activity and thereby blocks HIF1α degradation. Of note, LPS-induced PHD inhibition was neither due to cosubstrate depletion (oxygen or α-ketoglutarate) nor due to increased levels of reactive oxygen species, fumarate, and succinate. Instead, LPS inhibited PHD activity through NF-κB-mediated induction of the iron storage protein ferritin and subsequent decrease of intracellular available iron, a critical cofactor of PHD. Thus, hypoxia and LPS both induce HIF1α accumulation via PHD inhibition but deploy distinct molecular mechanisms (lack of cosubstrate oxygen versus deprivation of co-factor iron).

PMID:
26628374
DOI:
10.1016/j.celrep.2015.11.005
[Indexed for MEDLINE]
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