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J. Biol. Chem., Vol. 282, Issue 28, 20621-20633, July 13, 2007

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Heme Oxygenase-1 Protein Localizes to the Nucleus and Activates Transcription Factors Important in Oxidative Stress^*

Qing Lin¹, Sebastian Weis^¶1, Guang Yang¹, Yi-Hao Weng^¶, Rachel Helston^||, Kimberly Rish^||, Ann Smith^||, Jessica Bordner, Tobias Polte^¶, Frank Gaunitz^**, and Phyllis A. Dennery²

From the Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, the ^¶Department of Pediatrics, Stanford University, Palo Alto, California 94305, the ^||School of Biological Sciences, University of Missouri, Kansas City, Missouri 64110-2499, and ^**Universität Leipzig, Interdisziplinäres Zentrum, 04107 Leipzig, Germany

Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation, is an integral membrane protein of the smooth endoplasmic reticulum. However, we detected an HO-1 immunoreactive signal in the nucleus of cultured cells after exposure to hypoxia and heme or heme/hemopexin. Under these conditions, a faster migrating HO-1 immunoreactive band was enriched in nuclear extracts, suggesting that HO-1 was cleaved to allow nuclear entry. This was confirmed by the absence of immunoreactive signal with an antibody against the C terminus and the lack of a C-terminal sequence by gas chromatographymass spectrometry. Incubation with leptomycin B prior to hypoxia abolished nuclear HO-1 and the faster migrating band on Western analysis, suggesting that this process was facilitated by CRM1. Furthermore, preincubation with a cysteine protease inhibitor prevented nuclear entry of green fluorescent protein-labeled HO-1, demonstrating that protease-mediated C-terminal cleavage was also necessary for nuclear transport of HO-1. Nuclear localization was also associated with reduction of HO activity. HO-1 protein, whether it was enzymatically active or not, mediated activation of oxidant-responsive transcription factors, including activator protein-1. Nevertheless, nuclear HO-1 protected cells against hydrogen peroxide-mediated injury equally as well as cytoplasmic HO-1. We speculate that nuclear localization of HO-1 protein may serve to up-regulate genes that promote cytoprotection against oxidative stress.

Received for publication, August 18, 2006 , and in revised form, March 29, 2007.

^* This work was funded by National Institutes of Health Grant HL-58752 (to P. A. D.), the Research Incentive Funds of the University of Missouri-Kansas City (to A. S.), and the Hess and Mary L. Johnson funds from Stanford University (to P. A. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These three authors contributed equally to this work.

² To whom correspondence should be addressed: Division of Neonatology, Children's Hospital of Philadelphia 34th and Civic Center Blvd., Philadelphia, PA, 19104. Tel.: 215-590-1653; Fax: 267-426-5632; E-mail: dennery{at}email.chop.edu.

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