High-mobility group box 1, oxidative stress, and disease
Daolin Tang1, Rui Kang, Herbert J Zeh
1The DAMP Laboratory, Department of Surgery, G.27 Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA. lotzemt@upmc.edu
Antioxidants & Redox Signaling
|October 26, 2010
Summary
Oxidative stress impacts cellular components and triggers cell death pathways. High-mobility group box 1 (HMGB1) protein plays a key role in oxidative stress, influencing DNA repair and immune responses, with antioxidants offering protection.
Area of Science:
- Biochemistry
- Molecular Biology
- Immunology
Background:
- Oxidative stress, driven by reactive oxygen species, damages cellular macromolecules and initiates cell death pathways like apoptosis and necrosis.
- High-mobility group box 1 (HMGB1) protein, a nuclear protein and damage-associated molecular pattern, is central to oxidative stress responses, influencing cell survival and DNA repair.
- HMGB1's redox-sensitive nature, with key cysteines, dictates its function in disulfide bond formation and potential dimerization, impacting its biological activities.
Purpose of the Study:
- To elucidate the multifaceted roles of High-mobility group box 1 (HMGB1) protein in the context of oxidative stress.
- To investigate the redox-dependent modifications of HMGB1 and their implications for cellular signaling and immune responses.
- To explore the protective mechanisms of various antioxidants against oxidative stress-induced damage, focusing on HMGB1 modulation.
Main Methods:
- Analysis of HMGB1's redox-sensitive cysteines (Cys23, 45, 106) and their involvement in disulfide bond formation and dimerization under oxidative stress.
- Investigation of HMGB1's role in activating nicotinamide adenine dinucleotide phosphate oxidase and reactive oxygen species production in neutrophils.
- Assessment of the protective effects of antioxidants (ethyl pyruvate, quercetin, green tea, N-acetylcysteine, curcumin) in experimental models of sepsis and ischemia-reperfusion injury, evaluating their impact on HMGB1 release.
Main Results:
- Oxidative stress induces modifications in HMGB1, including disulfide bond formation (Cys23-Cys45) and potential Cys106-mediated dimerization, altering its function.
- HMGB1 contributes to increased reactive oxygen species production by activating nicotinamide adenine dinucleotide phosphate oxidase in neutrophils.
- Reduced and oxidized HMGB1 exhibit distinct extracellular signaling roles via receptors for advanced glycation end products and Toll-like receptors.
- Antioxidants demonstrated protective effects in experimental injury models, partly by attenuating HMGB1 release and systemic accumulation.
Conclusions:
- HMGB1 is a critical redox-sensitive protein linking oxidative stress to cellular damage, DNA repair, and immune activation.
- The redox state of HMGB1 dictates its diverse functions in intracellular and extracellular signaling pathways.
- Antioxidants provide therapeutic potential by mitigating oxidative stress and controlling detrimental HMGB1 activity in various injury settings.
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