HMGB1 in health and disease

Abstract

Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed high-mobility group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo. These include antibodies, peptide inhibitors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localization, structure, post-translational modification, and identification of additional partners will undoubtedly uncover additional secrets regarding HMGB1's multiple functions.

Keywords: Biology; DAMP; Disease; HMGB1.

Figure 1

Revised nomenclature for the HMG chromosomal proteins (Bustin, 2001)

Figure 2

The HMG-box proteins

Figure 3

Structure of the HMGB1 protein. (A) HMGB1 has two DNA-binding domains (A and B box) and an acidic C-terminal tail. (B) Helical secondary structure of A and B box domains (Thomas, 2001). (C) Intramolecular disulfide bond in the Adomain of HMGB1 (Wang et al., 2013e).

Figure 4

Nuclear HMGB1 acts as a DNA chaperone with DNA binding and bending activities that regulate a number of nuclear events.

Figure 5

Extracellular HMGB1 acts as a DAMP with cytokine and chemokine activities that regulate a number of cellular processes.

Figure 6

HMGB1 is released in two different ways: active secretion and passive release.

Figure 7

HMGB1 signals through receptors.

Figure 8

HMGB1 transcriptional regulation.

Figure 9

HMGB1 post-translational modification. (A) These modifications and regulations are critical for HMGB1 location and function. (B) The redox status of HMGB1 regulates its cytokine-inducing and chemokine activities.

Figure 10

HMGB1 cleavage and degradation.

Figure 11

Phenotype of the HMGB1 conditional knockout or knockin mouse in response to stress.

Figure 12

HMGB1 release in cell death