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

Siegert I, Schoedel J, Nairz M, Schatz V, Dettmer K, Dick C, Kalucka J, Franke K, Ehrenschwender M, Schley G, Beneke A, Sutter J, Moll M, Hellerbrand C, Wielockx B, Katschinski DM, Lang R, Galy B, Hentze MW, Koivunen P, Oefner PJ, Bogdan C, Weiss G, Willam C, Jantsch J (2015)

Publication Status: Published

Publication Type: Journal article, Original article

Publication year: 2015

Journal

Cell Reports Elsevier (Cell Press)

Publisher: Cell Press

Book Volume: 13

Pages Range: 2048 - 2055

DOI: 10.1016/j.celrep.2015.11.005

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 with CRIS profile

Jörg Sutter Lehrstuhl für Anorganische und Allgemeine Chemie Matthias Moll Lehrstuhl für Anorganische und Allgemeine Chemie Roland Lang Professur für Angeborene Immunität und Pathogenerkennung Christian Bogdan Lehrstuhl für Mikrobiologie und Infektionsimmunologie Carsten Willam Department of Medicine 4 – Nephrology and Hypertension

Involved external institutions

Oulun Yliopisto / University of Oulo FI Finland (FI) Georg-August-Universität Göttingen DE Germany (DE) Technische Universität Dresden DE Germany (DE) Medizinische Universität Innsbruck AT Austria (AT) Universität Regensburg DE Germany (DE) Universitätsklinikum Regensburg DE Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) European Molecular Biology Laboratory (EMBL) DE Germany (DE)

How to cite

APA:

Siegert, I., Schoedel, J., Nairz, M., Schatz, V., Dettmer, K., Dick, C.,... Jantsch, J. (2015). Ferritin-Mediated Iron Sequestration Stabilizes Hypoxia-Inducible Factor-1α upon LPS Activation in the Presence of Ample Oxygen. Cell Reports, 13, 2048 - 2055. https://doi.org/10.1016/j.celrep.2015.11.005

MLA:

Siegert, Isabel, et al. "Ferritin-Mediated Iron Sequestration Stabilizes Hypoxia-Inducible Factor-1α upon LPS Activation in the Presence of Ample Oxygen." Cell Reports 13 (2015): 2048 - 2055.

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