Back to Search
Start Over
Ferritin-Mediated Iron Sequestration Stabilizes Hypoxia-Inducible Factor-1α upon LPS Activation in the Presence of Ample Oxygen.
- Source :
-
Cell reports [Cell Rep] 2015 Dec 15; Vol. 13 (10), pp. 2048-55. Date of Electronic Publication: 2015 Nov 25. - Publication Year :
- 2015
-
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).<br /> (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Chromatography, High Pressure Liquid
Lipopolysaccharides toxicity
Mice
Mice, Inbred C57BL
Mice, Transgenic
Oxygen metabolism
Protein Processing, Post-Translational
Signal Transduction physiology
Spectrophotometry, Atomic
Tandem Mass Spectrometry
Ferritins metabolism
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Inflammation metabolism
Iron metabolism
Prolyl Hydroxylases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 13
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 26628374
- Full Text :
- https://doi.org/10.1016/j.celrep.2015.11.005