High-Mobility Group Box 1, Oxidative Stress, and Disease

Abstract

Oxidative stress and associated reactive oxygen species can modify lipids, proteins, carbohydrates, and nucleic acids, and induce the mitochondrial permeability transition, providing a signal leading to the induction of autophagy, apoptosis, and necrosis. High-mobility group box 1 (HMGB1) protein, a chromatin-binding nuclear protein and damage-associated molecular pattern molecule, is integral to oxidative stress and downstream apoptosis or survival. Accumulation of HMGB1 at sites of oxidative DNA damage can lead to repair of the DNA. As a redox-sensitive protein, HMGB1 contains three cysteines (Cys23, 45, and 106). In the setting of oxidative stress, it can form a Cys23-Cys45 disulfide bond; a role for oxidative homo-or heterodimerization through the Cys106 has been suggested for some of its biologic activities. HMGB1 causes activation of nicotinamide adenine dinucleotide phosphate oxidase and increased reactive oxygen species production in neutrophils. Reduced and oxidized HMGB1 have different roles in extracellular signaling and regulation of immune responses, mediated by signaling through the receptor for advanced glycation end products and=or Toll-like receptors. Antioxidants such as ethyl pyruvate, quercetin, green tea, N-acetylcysteine, and curcumin are protective in the setting of experimental infection=sepsis and injury including ischemia-reperfusion, partly through attenuating HMGB1 release and systemic accumulation. Antioxid. Redox Signal. 14, 1315-1335.

Chaperone-like Activity of High-Mobility Group Box 1 Protein and Its Role in Reducing the Formation of Polyglutamine Aggregates

“…Aggregation of a fragment of Htt protein directly causes free radical production in vivo (36), and inhibition of polyQ aggregation suppresses ROS (50,51). Oxidative potential is important for the nucleocytoplasmic translocation of HMGB1, and redox status of HMGB1 also affects its specific function (52). In our study, ROS generated by overexpression of 97Q-GFP induced translocation of nuclear HMGB1.…”

The Beclin 1 network regulates autophagy and apoptosis

“…HMGB1 is a chromatin-associated nuclear protein and extracellular damage-associated molecular pattern molecule. 47,48 Recently, we have shown that HMGB1 is a novel Beclin 1-binding protein important in sustaining autophagy. 25,49 Deletion, depletion or inhibition of HMGB1 in mouse embryonic fibroblasts or tumor cells markedly diminishes autophagy.…”

Real-time Kinetics of High-mobility Group Box 1 (HMGB1) Oxidation in Extracellular Fluids Studied by in Situ Protein NMR Spectroscopy

“…Using a unique NMR-based approach, we have investigated the kinetics of HMGB1 oxidation and the half-lives of all-thiol and disulfide HMGB1 species in serum, saliva, and cell culture medium. In this approach, salt-free lyophilized 15 Nlabeled all-thiol HMGB1 was dissolved in actual extracellular fluids, and the oxidation and clearance kinetics were monitored in situ by recording a series of heteronuclear 1 H-15 N correlation spectra. We found that the half-life depends significantly on the extracellular environment.…”

“…This 25-kDa protein, which is normally located in nuclei, is passively released during cell injury and necrosis and actively secreted by some cell types via a non-canonical pathway that bypasses the endoplasmic reticulum (13,14). Extracellular HMGB1 acts as a danger signal and inflammatory mediator via binding to cell surface receptors such as RAGE, TLR4 (Toll-like receptor 4), and CXCR4 (13)(14)(15)(16). Extracellular HMGB1/receptor interactions promote inflammation and angiogenesis via activation of NF-B (17,18) and tumor proliferation via activation of p44/ p42, p38, and SAPK/JNK MAPKs (19,20).…”

“…When released into the extracellular space, HMGB1 is initially in the reduced state ("all-thiol HMGB1") (see Fig. 1A) but becomes oxidized due to the oxidative environment (5,15,21). HMGB1 has three cysteine residues.…”