title: Heme oxygenase isoforms differ in their subcellular trafficking during hypoxia and are differentially modulated by cytochrome P450 reductase.
abstract: Heme oxygenase (HO) degrades heme in concert with NADPH cytochrome P450 reductase (CPR) which donates electrons to the reaction. Earlier studies reveal the importance of the hydrophobic carboxy-terminus of HO-1 for anchorage to the endoplasmic reticulum (ER) which facilitates the interaction with CPR. In addition, HO-1 has been shown to undergo regulated intramembrane proteolysis of the carboxy-terminus during hypoxia and subsequent translocation to the nucleus. Translocated nuclear HO-1 was demonstrated to alter binding of transcription factors and to alter gene expression. Little is known about the homologous membrane anchor of the HO-2 isoform. The current work is the first systematic analysis in a eukaryotic system that demonstrates the crucial role of the membrane anchor of HO-2 for localization at the endoplasmic reticulum, oligomerization and interaction with CPR. We show that although the carboxy-terminal deletion mutant of HO-2 is found in the nucleus, translocation of HO-2 to the nucleus does not occur under conditions of hypoxia. Thus, we demonstrate that proteolytic regulation and nuclear translocation under hypoxic conditions is specific for HO-1. In addition we show for the first time that CPR prevents this translocation and promotes oligomerization of HO-1. Based on these findings, CPR may modulate gene expression via the amount of nuclear HO-1. This is of particular relevance as CPR is a highly polymorphic gene and deficiency syndromes of CPR have been described in humans.
authors.affiliation: Department of Pharmacology, Toxicology and Clinical Pharmacy, University of Braunschweig-Institute of Technology, Braunschweig, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Linnenbaum
authors.forename: Mareike
authors.initials: M
authors.lastname: Busker
authors.forename: Jan R
authors.initials: JR
authors.lastname: Kraehling
authors.forename: Soenke
authors.initials: S
authors.lastname: Behrends
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002467:Cell Nucleus / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D057809:HEK293 Cells; D006419:Heme Oxygenase (Decyclizing) / Q000032:analysis* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000032:analysis* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism*; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D055503:Protein Multimerization; D021381:Protein Transport
chemical_list: D020033:Protein Isoforms; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2; D009251:NADPH-Ferrihemoprotein Reductase