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Nuclear Heat Shock Protein 72 as a Negative Regulator of Oxidative Stress (Hydrogen Peroxide)-Induced HMGB1 Cytoplasmic Translocation and Release¹

Daolin Tang^2,*, Rui Kang^2,, Weimin Xiao^*,, Lei Jiang^*, Meidong Liu^*, Yongzhong Shi^*, Kangkai Wang^*, Haichao Wang and Xianzhong Xiao^3,*

^* Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Changsha, Hunan, People’s Republic of China; Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; College of Optometry, University of Houston, Houston, TX 77204; and Department of Emergency Medicine, North Shore University Hospital, New York University School of Medicine, and Feinstein Institute for Medical Research, Manhasset, NY 11030

In response to inflammatory stimuli (e.g., endotoxin, proinflammatory cytokines) or oxidative stress, macrophages actively release a ubiquitous nuclear protein, high-mobility group box 1 (HMGB1), to sustain an inflammatory response to infection or injury. In this study, we demonstrated mild heat shock (e.g., 42.5°C, 1 h), or enhanced expression of heat shock protein (Hsp) 72 (by gene transfection) similarly rendered macrophages resistant to oxidative stress-induced HMGB1 cytoplasmic translocation and release. In response to oxidative stress, cytoplasmic Hsp72 translocated to the nucleus, where it interacted with nuclear proteins including HMGB1. Genetic deletion of the nuclear localization sequence (NLS) or the peptide binding domain (PBD) from Hsp72 abolished oxidative stress-induced nuclear translocation of Hsp72-NLS (but not Hsp72-PBD), and prevented oxidative stress-induced Hsp72-PBD-HMGB1 interaction in the nucleus. Furthermore, impairment of Hsp72-NLS nuclear translocation, or Hsp72-PBD-HMGB1 interaction in the nucleus, abrogated Hsp72-mediated suppression of HMGB1 cytoplasmic translocation and release. Taken together, these experimental data support a novel role for nuclear Hsp72 as a negative regulator of oxidative stress-induced HMGB1 cytoplasmic translocation and release.

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 This work was supported by Grants 30500485 (to D.T.) and 30330280 (to X.X.) from the National Natural Sciences Foundation of China, the Major National Basic Research Program of China Grant G2000056908 (to X.X.), the Specialized Research Fund for the Doctoral Program of Higher Education of China Grant 20060533009 (to X.X.), and the Innovative Program of Central South University for Post-graduate Research Grant 2005-75239 (to D.T.), and in part by National Institutes of Health Grants (National Institute of General Medical Sciences) R01GM063075 and R01GM070817 (to H.W.).

² D.T. and R.K. contributed equally to this paper.

³ Address correspondence and reprint requests to Dr. Xianzhong Xiao, Department of Pathophysiology, Xiangya School of Medicine, Central South University, 110 Xiangya Road, Changsha, Hunan, People’s Republic of China. E-mail address: xianzhongxiao{at}xysm.net

⁴ Abbreviations used in this paper: ROS, reactive oxygen species; HMGB1, high mobility group box 1 protein; Hsp, heat shock protein; LDH, lactate dehydrogenase; NLS, nuclear localization sequence; PBD, peptide binding domain.

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