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

作者：Isabel Siegert, Johannes Schödel, Manfred Nairz, Valentin Schatz, Katja Dettmer, Christopher J. 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 · 发表于：Cell Reports · 年份：2015 · DOI：10.1016/j.celrep.2015.11.005 · 被引用次数：109 · 研究领域：Cancer, Hypoxia, and Metabolism、Peroxisome Proliferator-Activated Receptors、RNA modifications and cancer

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).