Cell Reports (Dec 2015)
Ferritin-Mediated Iron Sequestration Stabilizes Hypoxia-Inducible Factor-1α upon LPS Activation in the Presence of Ample Oxygen
- Isabel Siegert,
- Johannes Schödel,
- Manfred Nairz,
- Valentin Schatz,
- Katja Dettmer,
- Christopher Dick,
- Joanna Kalucka,
- Kristin Franke,
- Martin Ehrenschwender,
- Gunnar Schley,
- Angelika Beneke,
- Jörg Sutter,
- Matthias Moll,
- Claus Hellerbrand,
- Ben Wielockx,
- Dörthe M. Katschinski,
- Roland Lang,
- Bruno Galy,
- Matthias W. Hentze,
- Peppi Koivunen,
- Peter J. Oefner,
- Christian Bogdan,
- Günter Weiss,
- Carsten Willam,
- Jonathan Jantsch
Affiliations
- Isabel Siegert
- Mikrobiologisches Institut – Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany
- Johannes Schödel
- Department of Nephrology and Hypertension, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU), 91054 Erlangen, Germany
- Manfred Nairz
- Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Valentin Schatz
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg, 93053 Regensburg, Germany
- Katja Dettmer
- Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany
- Christopher Dick
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg, 93053 Regensburg, Germany
- Joanna Kalucka
- Department of Nephrology and Hypertension, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU), 91054 Erlangen, Germany
- Kristin Franke
- Heisenberg Research Group, Department of Clinical Pathobiochemistry, Institute of Clinical Chemistry and Laboratory Medicine, University of Technology, 01307 Dresden, Germany
- Martin Ehrenschwender
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg, 93053 Regensburg, Germany
- Gunnar Schley
- Department of Nephrology and Hypertension, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU), 91054 Erlangen, Germany
- Angelika Beneke
- Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University Göttingen, 37073 Göttingen, Germany
- Jörg Sutter
- Department of Chemistry and Pharmacy, Inorganic Chemistry, Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, 91058 Erlangen, Germany
- Matthias Moll
- Department of Chemistry and Pharmacy, Inorganic Chemistry, Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, 91058 Erlangen, Germany
- Claus Hellerbrand
- Department of Internal Medicine I, University of Regensburg, 93053 Regensburg, Germany
- Ben Wielockx
- Heisenberg Research Group, Department of Clinical Pathobiochemistry, Institute of Clinical Chemistry and Laboratory Medicine, University of Technology, 01307 Dresden, Germany
- Dörthe M. Katschinski
- Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University Göttingen, 37073 Göttingen, Germany
- Roland Lang
- Mikrobiologisches Institut – Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany
- Bruno Galy
- Division of Virus-Associated Carcinogenesis, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Matthias W. Hentze
- European Molecular Biology Laboratory, 69120 Heidelberg, Germany
- Peppi Koivunen
- Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, 90014 Oulu, Finland
- Peter J. Oefner
- Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany
- Christian Bogdan
- Mikrobiologisches Institut – Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany
- Günter Weiss
- Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Carsten Willam
- Department of Nephrology and Hypertension, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU), 91054 Erlangen, Germany
- Jonathan Jantsch
- Mikrobiologisches Institut – Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany
- DOI
- https://doi.org/10.1016/j.celrep.2015.11.005
- Journal volume & issue
-
Vol. 13,
no. 10
pp. 2048 – 2055
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).
