Iron-regulatory proteins limit hypoxia-inducible factor-2alpha expression in iron deficiency.
Hypoxia stimulates erythropoiesis, the major iron-utilization pathway. We report the discovery of a conserved, functional iron-responsive element (IRE) in the 5' untranslated region of the messenger RNA encoding endothelial PAS domain protein-1, EPAS1 (also called hypoxia-inducible factor-2alpha, HIF2alpha). Via this IRE, iron regulatory protein binding controls EPAS1 mRNA translation in response to cellular iron availability. Our results uncover a regulatory link that permits feedback control between iron availability and the expression of a key transcription factor promoting iron utilization. They also show that an IRE that is structurally distinct from, for example, the ferritin mRNA IRE and that has been missed by in silico approaches, can mediate mechanistically similar responses.
Sanchez
Mayka
M
Molecular Medicine Partnership Unit, Im Neuenheimer Feld 153, 69120 Heidelberg, Germany.
Galy
Bruno
B
Muckenthaler
Martina U
MU
Hentze
Matthias W
MW
D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D000090463:Iron Deficiencies; D019189:Iron Metabolism Disorders; D035925:Iron-Regulatory Proteins / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D020218:Response Elements; D014157:Transcription Factors / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D035925:Iron-Regulatory Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1