Ferritin-Mediated Iron Sequestration Stabilizes Hypoxia-Inducible Factor-1 alpha upon LPS Activation in the Presence of Ample Oxygen
2015 | journal article. A publication with affiliation to the University of Göttingen.
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Ferritin-Mediated Iron Sequestration Stabilizes Hypoxia-Inducible Factor-1 alpha upon LPS Activation in the Presence of Ample Oxygen
Siegert, I.; Schoedel, J.; Nairz, M.; Schatz, V.; Dettmer, K.; Dick, C. & Kalucka, J. et al. (2015)
Cell Reports, 13(10) pp. 2048-2055. DOI: https://doi.org/10.1016/j.celrep.2015.11.005
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Details
- Authors
- Siegert, Isabel; Schoedel, Johannes; Nairz, Manfred; Schatz, Valentin; Dettmer, Katja; Dick, Christopher; Kalucka, Joanna; Franke, Kristin; Ehrenschwender, Martin; Schley, Gunnar; Beneke, Angelika; Sutter, Joerg; Moll, Matthias; Hellerbrand, Claus; Wielockx, Ben; Katschinski, Doerthe Magdalena; Lang, Roland; Galy, Bruno; Hentze, Matthias W.; Koivunen, Peppi; Oefner, Peter J.; Bogdan, Christian; Weiss, Guenter; Willam, Carsten; Jantsch, Jonathan
- Abstract
- Both hypoxic and inflammatory conditions activate transcription factors such as hypoxia-inducible factor (HIF)-1 alpha and nuclear factor (NF)-kappa B, which play a crucial role in adaptive responses to these challenges. In dendritic cells (DC), lipopolysaccharide (LPS)-induced HIF1 alpha accumulation requires NF-kappa B signaling and promotes inflammatory DC function. The mechanisms that drive LPS-induced HIF1 alpha accumulation under normoxia are unclear. Here, we demonstrate that LPS inhibits prolyl hydroxylase domain enzyme (PHD) activity and thereby blocks HIF1 alpha degradation. Of note, LPS-induced PHD inhibition was neither due to cosubstrate depletion (oxygen or alpha-ketoglutarate) nor due to increased levels of reactive oxygen species, fumarate, and succinate. Instead, LPS inhibited PHD activity through NF-kappa B-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 HIF1 alpha accumulation via PHD inhibition but deploy distinct molecular mechanisms (lack of cosubstrate oxygen versus deprivation of co-factor iron).
- Issue Date
- 2015
- Status
- published
- Publisher
- Cell Press
- Journal
- Cell Reports
- ISSN
- 2211-1247