The non-canonical functions of the heme oxygenases

Oncotarget. 2016 Oct 18;7(42):69075-69086. doi: 10.18632/oncotarget.11923.


Heme oxygenase (HO) isoforms catalyze the conversion of heme to carbon monoxide (CO) and biliverdin with a concurrent release of iron, which can drive the synthesis of ferritin for iron sequestration. Most of the studies so far were directed at evaluating the protective effect of these enzymes because of their ability to generate antioxidant and antiapoptotic molecules such as CO and bilirubin. Recent evidences are suggesting that HO may possess other important physiological functions, which are not related to its enzymatic activity and for which we would like to introduce for the first time the term "non canonical functions". Recent evidence suggest that both HO isoforms may form protein-protein interactions (i.e. cytochrome P450, adiponectin, CD91) thus serving as chaperone-like protein. In addition, truncated HO-1 isoform was localized in the nuclear compartment under certain experimental conditions (i.e. excitotoxicity, hypoxia) regulating the activity of important nuclear transcription factors (i.e. Nrf2) and DNA repair. In the present review, we discuss three potential signaling mechanisms that we refer to as the non-canonical functions of the HO isoforms: protein-protein interaction, intracellular compartmentalization, and extracellular secretion. The aim of the present review is to describe each of this mechanism and all the aspects warranting additional studies in order to unravel all the functions of the HO system.

Keywords: extracellular space; heme oxygenase; non-canonical functions; nuclear translocation; protein-protein interaction.

Publication types

  • Review

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Antioxidants / chemistry
  • Apoptosis
  • Carbon Monoxide / chemistry
  • Cell Nucleus / metabolism
  • Cytochrome P-450 Enzyme System / metabolism
  • DNA Repair
  • Extracellular Space / metabolism
  • Heme Oxygenase-1 / physiology*
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-1 / metabolism
  • NF-E2-Related Factor 2 / metabolism
  • Protein Binding
  • Protein Interaction Mapping
  • Protein Isoforms / physiology


  • Antioxidants
  • LRP1 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-1
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Protein Isoforms
  • Carbon Monoxide
  • Cytochrome P-450 Enzyme System
  • HMOX1 protein, human
  • Heme Oxygenase-1