The non-canonical functions of the heme oxygenases

Luca Vanella, Ignazio Barbagallo, Daniele Tibullo, Stefano Forte, Agata Zappalà and Giovanni Li Volti _

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Oncotarget. 2016; 7:69075-69086. https://doi.org/10.18632/oncotarget.11923

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Luca Vanella1,*, Ignazio Barbagallo1,*, Daniele Tibullo2, Stefano Forte3,4, Agata Zappalà3 and Giovanni Li Volti3,5

1 Department of Drug Sciences, University of Catania, Catania, Italy

2 Division of Haematology, AOU “Policlinico - Vittorio Emanuele”, University of Catania, Catania, Italy

3 Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy

4 Istituto Oncologico del Mediterraneo Ricerca srl Viagrande, Catania, Italy

5 EuroMediterranean Institute of Science and Technology, Palermo, Italy

* The first and second author contributed equally to this manuscript

Correspondence to:

Giovanni Li Volti, email:

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

Received: June 02, 2016 Accepted: September 05, 2016 Published: September 09, 2016


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.

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