title: Ferritin-Mediated Iron Sequestration Stabilizes Hypoxia-Inducible Factor-1α upon LPS Activation in the Presence of Ample Oxygen.
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).
authors.affiliation: Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Siegert
authors.affiliation: Department of Nephrology and Hypertension, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU), 91054 Erlangen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schödel
authors.affiliation: Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Manfred
authors.initials: M
authors.lastname: Nairz
authors.affiliation: Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Valentin
authors.initials: V
authors.lastname: Schatz
authors.affiliation: Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Dettmer
authors.affiliation: Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Dick
authors.affiliation: Department of Nephrology and Hypertension, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU), 91054 Erlangen, Germany.
authors.forename: Joanna
authors.initials: J
authors.lastname: Kalucka
authors.affiliation: Heisenberg Research Group, Department of Clinical Pathobiochemistry, Institute of Clinical Chemistry and Laboratory Medicine, University of Technology, 01307 Dresden, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Franke
authors.affiliation: Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Ehrenschwender
authors.affiliation: Department of Nephrology and Hypertension, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU), 91054 Erlangen, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Schley
authors.affiliation: Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University Göttingen, 37073 Göttingen, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Beneke
authors.affiliation: Department of Chemistry and Pharmacy, Inorganic Chemistry, Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, 91058 Erlangen, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Sutter
authors.affiliation: Department of Chemistry and Pharmacy, Inorganic Chemistry, Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, 91058 Erlangen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Moll
authors.affiliation: Department of Internal Medicine I, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Hellerbrand
authors.affiliation: Heisenberg Research Group, Department of Clinical Pathobiochemistry, Institute of Clinical Chemistry and Laboratory Medicine, University of Technology, 01307 Dresden, Germany.
authors.forename: Ben
authors.initials: B
authors.lastname: Wielockx
authors.affiliation: Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University Göttingen, 37073 Göttingen, Germany.
authors.forename: Dörthe M
authors.initials: DM
authors.lastname: Katschinski
authors.affiliation: Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Lang
authors.affiliation: Division of Virus-Associated Carcinogenesis, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Bruno
authors.initials: B
authors.lastname: Galy
authors.affiliation: European Molecular Biology Laboratory, 69120 Heidelberg, Germany.
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Hentze
authors.affiliation: Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, 90014 Oulu, Finland.
authors.forename: Peppi
authors.initials: P
authors.lastname: Koivunen
authors.affiliation: Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Oefner
authors.affiliation: Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Bogdan
authors.affiliation: Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Günter
authors.initials: G
authors.lastname: Weiss
authors.affiliation: Department of Nephrology and Hypertension, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU), 91054 Erlangen, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Willam
authors.affiliation: 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.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Jantsch
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005293:Ferritins / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010100:Oxygen / Q000378:metabolism; D064828:Prolyl Hydroxylases / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction / Q000502:physiology; D013054:Spectrophotometry, Atomic; D053719:Tandem Mass Spectrometry
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008070:Lipopolysaccharides; D005293:Ferritins; D007501:Iron; D064828:Prolyl Hydroxylases; D010100:Oxygen