Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

High Mobility Group Box B1

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101643

Synonyms

Historical Background

High mobility group (HMG) chromosomal protein family was first discovered in 1973 (Goodwin and Johns 1973; Goodwin et al. 1973). At that time, the name HMG was defined according to their high electrophoretic mobility in polyacrylamide gels. Then in 1976, α-helix structures of HMGs were identified (Baker et al. 1976; Cary et al. 1976). In 2001, the domains of HMG1 were characterized (Thomas 2001), and at the same year, the HMG Chromosomal Protein Nomenclature Committee recategorized the proteins into three superfamilies: HMGB (formerly known as HMG-1/2), HMGA (formerly known as HMG-14/17), and HMGN (formerly known as HMG-1/Y) (Bustin 2001). Up to date, the functions of HMGB family members have been unveiled for years (Grosschedl et al. 1994; Zlatanova et al. 1999; Bianchi and Agresti 2005).

HMGB1 Structure

HMGB1 is a highly conserved protein, encoded on human chromosome 13q12–13, and is one of the HMGB family members (HMGB 1, 2, 3, and 4) with a molecular weight 30 kDa and consists of 215 amino acids and three domains (Chen et al. 2013). While the three domains form HMGB A box (9–79 aa), HMG B box (95–163 aa), and the C-terminal acidic tail (186–215 aa) (Bianchi et al. 1992). A and B are DNA-binding domains; C-tail functions as transcription stimulation (Rojas et al. 2014).

HMGB1 Acceptors

The receptors of HMGB1 include receptor for advanced glycation end product (RAGE) (Fages et al. 2000), the toll-like receptors (TLRs, such as TLR2, 4, and 9) (Yang et al. 2010; Yang et al. 2012), integrin (Orlova et al. 2007), α-synuclein filaments (Lindersson et al. 2004), proteoglycans (e.g., heparin sulfate (Xu et al. 2011)), CD24 (Chen et al. 2009), the T-cell immunoglobulin domain and mucin domain-3 (TIM-3) (Chiba et al. 2012), the member of the G protein-coupled receptors CXCR4 (Penzo et al. 2010), N-methyl-D-aspartate receptor (NMDAR) (Pedrazzi et al. 2012), Mac1 (macrophage antigen complex 1, also known as complement receptor 3, CD11b/CD18, or αM2) (Gao et al. 2011), and the triggering receptor expressed on myeloid cells-1 (TREM1) (Bouchon et al. 2001). HMGB1 exerts different functions with different receptors.

HMGB1 Cellular in Physiology and Function

In nucleus, HMGB1 acts as a DNA chaperone and maintains nucleosome assembly, chromatin replication (Bonne-Andrea et al. 1984; Topalova et al. 2008), and DNA repair (Lange et al. 2008). In cytoplasm in the normal organs, HMGB1 acts as a positive factor to protect cells from injury (Kang et al. 2014a). Mice are most likely to be sensitive to liver ischemia/reperfusion (Huang et al. 2014), pancreatitis (Kang et al. 2014b), and sepsis (Yanai et al. 2013) if HMGB1 is knockedout, respectively.

HMGB1 and Diseases

Sepsis The secretion and release of HMGB1 can lead to sepsis which may be induced by lipopolysaccharide (LPS), a major component of Gram-negative bacteria (Wang et al. 1999).

Ischemia/reperfusion injury HMGB1 is also associated with ischemia reperfusion injury in liver (Watanabe et al. 2005), heart (Huang et al. 2007), kidney (Wu et al. 2007), intestine (Hagiwara et al. 2010), and brain (Hayakawa et al. 2008).

Aging In the neurons of the aged brain, HMGB1 is downregulated whereas it is upregulated in astrocytes, indicating that HMGB1 expression during aging is differentially regulated between neurons and astrocytes (Enokido et al. 2008). HMGB1 binds to several receptors such as RAGE, TLR-2, and TLR-4 in microglia, which in turn accelerates neuroinflammation, injury, and further HMGB1 release (Gao et al. 2011).

Huntington’s disease HMGB1 may play a role in poly-induced neuronal cell toxicity. In addition, downregulation of HMGB1 in the nucleus results in the DNA double-strand break (DDSB)-mediated neuronal damage in Huntington’s disease (Qi et al. 2007).

Alzheimer’s disease HMGB1 can impair memory by RAGE and TLR4 (Mazarati et al. 2011) and aggregates to neurotic plaques, leading to binding Aβ to inhibit the phagocytosis and degradation of Aβ by microglial cells (Takata et al. 2003).

Parkinson’s disease In Parkinson’s disease, HMGB1 binds its receptor α-synuclein reducing autophagy (Song et al. 2014).

Epilepsy Epilepsy is a group of neurological diseases characterized by epileptic seizures. HMGB1 promotes seizures in a TLR4-dependent pathway by triggering tissue damage and the inflammatory response (Kleen and Holmes 2010).

Heart and vascular disease HMGB1 involves the inflammatory response in cardiovascular diseases via HMGB1-RAGE pathway (Volz et al. 2010).

Kidney disease HMGB1 is high-expressed in some kidney diseases by binding its receptors RAGE/TLR4 (Sato et al. 2008).

Autoimmune disease For instance, the expression of HMGB1 is increased at the site of joint inflammation in rheumatoid arthritis, including the synovial tissue and synovial fluid (Kokkola et al. 2002).

Diabetes HMGB1 release can lead to insulitis progression and diabetes onset in a nitric oxide–dependent manner by binding its receptors RAGE, TLR4, and TLR2 (Steer et al. 2006).

Lung disease HMGB1 is a key inflammatory factor for lung disease. A high level of HMGB1 in lung/serum can be observed if patients suffer from asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome, lung fibrosis, and pneumonia (Kang et al. 2014a).

Cancer HMGB1 plays a critical role in a number of cancers, including colorectal, breast, lung, prostate, cervical, skin, kidney, gastric, pancreatic, osteosarcoma, and liver cancer in which HMGB1 involves in cancer cell proliferation, differentiation, angiogenesis, metastasis, inflammatory response, and immunofunction (Wang et al. 2015).

Others HMGB1 will be released by the activation of RAGE and TLR4 pathway when the digestive diseases and the cell injury occur (Kao et al. 2008; Radin et al. 2011; Nadatani et al. 2013).

Summary

In conclusion, HMGB1 is a family member of HMGs, acts as a key factor for sustaining nucleic homeostasis, physical functions, and also plays a critical role in response to injury, inflammation, and pathological process. The pathway depends on its receptors, RAGE, TLRs, integrin, α-synuclein filaments, proteoglycans, CD24, TIM-3, CXCR4, NMDAR, Mac1, and TREM1. It may be a potential target for treating the relative diseases (Fig. 1).
High Mobility Group Box B1, Fig. 1

Profile of HMGB1, its acceptors, physical functions, and role in diseases

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Laboratory of Chinese Herbal Pharmacology, Oncology Center, Renmin HospitalHubei University of MedicineShiyanChina