High Mobility Group Box 1: Biological Functions and Relevance in Oxidative Stress Related Chronic Diseases

Abstract

In the early 1970s, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and named high-mobility group (HMG) proteins. High-mobility group box 1 (HMGB1) is the most studied HMG protein that detects and coordinates cellular stress response. The biological function of HMGB1 depends on its subcellular localization and expression. It plays a critical role in the nucleus and cytoplasm as DNA chaperone, chromosome gatekeeper, autophagy maintainer, and protector from apoptotic cell death. HMGB1 also functions as an extracellular alarmin acting as a damage-associated molecular pattern molecule (DAMP). Recent findings describe HMGB1 as a sophisticated signal of danger, with a pleiotropic function, which is useful as a clinical biomarker for several disorders. HMGB1 has emerged as a mediator in acute and chronic inflammation. Furthermore, HMGB1 targeting can induce beneficial effects on oxidative stress related diseases. This review focus on HMGB1 redox status, localization, mechanisms of release, binding with receptors, and its activities in different oxidative stress-related chronic diseases. Since a growing number of reports show the key role of HMGB1 in socially relevant pathological conditions, to our knowledge, for the first time, here we analyze the scientific literature, evaluating the number of publications focusing on HMGB1 in humans and animal models, per year, from 2006 to 2021 and the number of records published, yearly, per disease and category (studies on humans and animal models).

Keywords: cancer; cardiovascular diseases; damage-associated molecular pattern molecules; diabetes; high-mobility group box 1; inflammation; neurological diseases; oxidative stress related chronic diseases; respiratory diseases.

Figure 1

Schematic representation of HMGB1 structure. HMGB1 has 215 amino acids organized in two proximal homologous DNA binding domains, A-box, B-box, and a C-terminal acidic tail with repeated acid residues. HMGB1 has two nuclear localization signals (NLS1 and NLS2), one TLR-binding domain and one RAGE-binding domain.

Figure 2

Three HMGB1 redox forms and their functions. HMGB1 has three conserved cysteines (C) in positions 23, 45, and 106. C23 and C45 can form an intermolecular disulfide bond, and C106 remains in reduced thiol state. The three redox forms of HMGB1, all-thiol-HMGB1, disulfide-HMGB1, and oxidized HMGB1 are generated by the different status of each C. HMGB1 in each redox status has a different function.

Figure 3

The different roles of HMGB1 depend on its localization. Nuclear HMGB1 DNA acts as a chaperone and it has activities of DNA binding and bending. Extracellular HMGB1 activates cytokine and chemokine pathways and functions as damage-associated molecular patterns (DAMPs).

Figure 4

Overall number of publications involving HMGB1 among humans and other animal models per year.

Figure 5

Number of records published yearly between 2006 and 2021 per disease (studies on human subjects).

Figure 6

Number of records published yearly between 2006 and 2021 per disease (studies on animal models).

Figure 7

Schematic representation of the effects of HMGB1 in cancer.

Figure 8

Schematic representation of the role of HMGB1 in neurological disorders (a) and the effect of HMGB1 blockade (b).

Figure 9

Schematic representation of the dual role of HMGB1 in cardiac disorders. Effects of HMGB1 in ischemia, MI, and inflammation (a) cardiac remodeling and repair (b).

Figure 10

Schematic representation of the role of HMGB1 in respiratory diseases.