Siegert, Isabel and Schoedel, Johannes and Nairz, Manfred and Schatz, Valentin and Dettmer, Katja and Dick, Christopher and Kalucka, Joanna and Franke, Kristin and Ehrenschwender, Martin and Schley, Gunnar and Beneke, Angelika and Sutter, Joerg and Moll, Matthias and Hellerbrand, Claus and Wielockx, Ben and Katschinski, Doerthe M. and Lang, Roland and Galy, Bruno and Hentze, Matthias W. and Koivunen, Peppi and Oefner, Peter J. and Bogdan, Christian and Weiss, Guenter and Willam, Carsten and Jantsch, Jonathan (2015) Ferritin-Mediated Iron Sequestration Stabilizes Hypoxia-Inducible Factor-1 alpha upon LPS Activation in the Presence of Ample Oxygen. CELL REPORTS, 13 (10). pp. 2048-2055. ISSN 2211-1247,
Full text not available from this repository. (Request a copy)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).
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NF-KAPPA-B; FACTOR 1-ALPHA; HIF-1-ALPHA; LIPOPOLYSACCHARIDE; DEGRADATION; MACROPHAGES; INHIBITION; IMMUNITY; HIF-1; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) Medicine > Lehrstuhl für Innere Medizin I Medicine > Lehrstuhl für Medizinische Mikrobiologie und Hygiene |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 29 Apr 2019 08:16 |
| Last Modified: | 29 Apr 2019 08:16 |
| URI: | https://pred.uni-regensburg.de/id/eprint/4283 |
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