HMGB1

What is HMGB1 protein?

HMGB1 gene (high mobility group box 1) is a protein coding gene which situated on the long arm of chromosome 13 at locus 13q12. HMGB1 is a multifunctional protein that binds to DNA in the nucleus and is involved in a variety of cellular processes, including transcriptional regulation, DNA replication and repair, telomere maintenance, and nucleosome assembly. It has three functional regions: A-box, B-box and acid C-terminal. These regions are involved in DNA binding and transcriptional regulation. The N-terminal of HMGB1 contains heparin binding sites, and the C-terminal contains acidic amino acids that regulate the binding affinity of HMGB1 to DNA. The HMGB1 protein is consisted of 215 amino acids and HMGB1 molecular weight is approximately 24.9 kDa.

What is the function of HMGB1 protein?

HMGB1 protein is a multifunctional nucleoprotein that binds to DNA in cells and is involved in key cellular processes such as regulating gene expression, DNA replication and repair, telomere maintenance and nucleosome assembly. Outside the cell, HMGB1 acts as a damage-associated molecular pattern (DAMP), triggering inflammatory and immune responses by binding to a variety of receptors such as RAGE and TLRs, affecting cell proliferation, differentiation, and migration. In addition, HMGB1 is also involved in the regulation of autophagy, cell death and tissue repair, and its abnormal expression or function is closely related to the occurrence and development of a variety of diseases.

HMGB1 related signaling pathway

HMGB1 is a highly conserved nuclear protein that plays crucial roles in various biological processes, including DNA repair, transcription regulation, and inflammation. When released extracellularly, it acts as a damage-associated molecular pattern (DAMP) and can activate multiple signaling pathways, such as Toll-like receptors (TLRs), particularly TLR2 and TLR4, leading to the activation of downstream inflammatory responses through NF-κB and MAPK pathways. Additionally, HMGB1 can interact with RAGE (Receptor for Advanced Glycation End Products) and TIM family members, further amplifying inflammatory signals and contributing to tissue repair or fibrosis depending on the context. This multifaceted role of HMGB1 in both physiological and pathological conditions underscores its importance in immune regulation and disease progression.

HMGB1 related diseases

HMGB1 (High Mobility Group Box 1) is a multifunctional protein involved in various biological processes such as DNA repair, transcription regulation, and inflammation. Elevated levels of HMGB1 have been implicated in numerous diseases, including sepsis, rheumatoid arthritis, systemic lupus erythematosus, cancer, and neurodegenerative disorders such as Alzheimer's disease. In these conditions, extracellular HMGB1 acts as a damage-associated molecular pattern (DAMP), triggering pro-inflammatory responses through interactions with receptors like TLR2, TLR4, and RAGE. These interactions can lead to the activation of signaling pathways such as NF-κB and MAPK, exacerbating inflammation and tissue damage. Consequently, targeting HMGB1 or its signaling pathways has emerged as a potential therapeutic strategy for managing these diseases.

Fig1. Therapeutic strategies to target HMGB1 in cancer studies. (Sourour Idoudi, 2023)

Bioapplications of HMGB1

In clinical applications, HMGB1 is a potential biomarker, and its level changes in blood, urine or tissue are closely related to the occurrence, development and prognosis of a variety of diseases. For example, in patients with acute ischemic stroke and in model animals, elevated levels of HMGB1 correlate with the extent of inflammatory response and nerve damage. In addition, HMGB1 has shown potential therapeutic value in promoting immune cell recruitment, regulating the inflammatory microenvironment, and influencing tumor growth and metastasis. The versatility of HMGB1 makes it an important target for drug development. For example, through the use of strategies such as anti-HMGB1 antibodies, soluble RAGE (s-RAGE), small molecule inhibitors, and peptide mimics, HMGB1 expression, release, or activity can be inhibited, thus playing a role in the treatment of hematological malignancies, promoting anti-tumor immune response, inhibiting inflammatory response, and enhancing chemotherapy drug sensitivity.

Case Study 1: Sung-Chun Tang, 2013

This study aims to investigate the role of plasma sRAGE and HMGB1 in acute ischemic stroke (IS) patients and mice with focal ischemic stroke. Plasma sRAGE and HMGB1 levels were measured in IS patients and a mouse model. Both markers increased significantly within 48 hours post-stroke, with sRAGE predicting functional outcome at 3 months. Binding of HMGB1 to sRAGE increased post-IS in both groups. Recombinant sRAGE reduced immune cell infiltration, improved mouse outcomes, protected neurons from cell death, and mitigated HMGB1's harmful effects.

Fig1. Plasma levels of HMGB1 are significantly higher in IS patients than in controls at all 3 time points.

Fig2. Administration of rHMGB1 results in the worst survival rate among all study groups.

Case Study 2: Takamitsu Sasaki, 2024

In ulcerative colitis (UC), which is linked to colorectal cancer (CRC), high levels of high-mobility group box-1 (HMGB1) are found, but its exact role in UC-related CRC is not well understood. This study explored HMGB1's role in both UC-associated and sporadic CRC. Here HMGB1 levels in the mucosa rose over time in mouse models of colon carcinogenesis and colitis. There was an initial increase and subsequent decrease in activated CD8+ cells, a rise in exhausted CD8+ cells, and an increase in regulatory CD8+ cells. Researchers also noted a decline in naïve CD8+ cells and mucosal epithelial differentiation. In vitro, HMGB1 prompted a metabolic shift from oxidative phosphorylation to glycolysis in CD8+ cells and intestinal epithelial cells. In human UC dysplasia and CRC, we observed higher mucosal HMGB1, lower activated CD8+ cells, and impaired mucosal epithelial differentiation, except in active UC mucosa where activated CD8+ cells were more abundant.

Fig3. Effects of HMGB1 on intestinal epithelial cells growth.

Fig4. HMGB1 protein levels assessed by ELISA.

HMGB1 has several biochemical functions, for example, C-X-C chemokine binding,DNA binding, bending,DNA polymerase binding. Some of the functions are cooperated with other proteins, some of the functions could acted by HMGB1 itself. We selected most functions HMGB1 had, and list some proteins which have the same functions with HMGB1. You can find most of the proteins on our site.

HMGB1 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with HMGB1 here. Most of them are supplied by our site. Hope this information will be useful for your research of HMGB1.

HTT;AGTRAP;MSH2;CSNK1A1