Nuclear heat shock protein 72 as a negative regulator of oxidative stress (hydrogen peroxide)-induced HMGB1 cytoplasmic translocation and release.
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 degrees 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-DeltaNLS (but not Hsp72-DeltaPBD), and prevented oxidative stress-induced Hsp72-DeltaPBD-HMGB1 interaction in the nucleus. Furthermore, impairment of Hsp72-DeltaNLS nuclear translocation, or Hsp72-DeltaPBD-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.
Tang
Daolin
D
Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Changsha, Hunan, People's Republic of China.
Kang
Rui
R
Xiao
Weimin
W
Jiang
Lei
L
Liu
Meidong
M
Shi
Yongzhong
Y
Wang
Kangkai
K
Wang
Haichao
H
Xiao
Xianzhong
X
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D050884:HSP72 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D047468:Immunoprecipitation; D020014:K562 Cells; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D011794:Quercetin / Q000494:pharmacology
D024243:HMGB1 Protein; D050884:HSP72 Heat-Shock Proteins; D011794:Quercetin; D006861:Hydrogen Peroxide