HMGB1

Background

High Mobility Group Box 1 (HMGB1), encoded by the HMGB1 gene, belongs to the high mobility group (HMG) family. HMGB1 is a non-histone chromosomal protein that exhibits high mobility due to its lack of a fixed tertiary structure. HMGB1 is ubiquitously present in the nucleus of eukaryotic cells, where it binds DNA with high affinity through its two DNA-binding domains, the A box and B box, and a flexible acidic tail, facilitating transcriptional regulation, DNA repair, and maintenance of genome stability. Outside cells, HMGB1 acts as a damage-associated molecular pattern (DAMP), functioning as a pro-inflammatory cytokine or chemokine, eliciting immune responses and promoting inflammation in various pathological conditions, including sepsis, arthritis, ischemia-reperfusion injury, neurodegenerative diseases, autoimmune diseases, and cancer progression.

Its Gene ID: 3146, UniProtKB ID: P09429, and OMIM ID: 163905.

Fig.1 The structure and modification of HMGB1.¹

Active HMGB1 Secretion and Passive HMGB1 Release

Active secretion of HMGB1 involves two main models:

• Firstly, stimulation of target cells by various stressors like ROS, RNS, and calcium ions can trigger HMGB1 release into the extracellular space. This process is mediated by signaling pathways involving molecules such as XPO1, TNF, NF-κB, and Notch receptors.
• Secondly, HMGB1 can be packaged into intracellular vesicles like lysosomes or autophagosomes and then released through the fusion of these vesicles with the plasma membrane.

Additionally, secretion may involve secretory lysosomes and cell-cell interactions, further influencing HMGB1's role as a pro-inflammatory cytokine and DAMP in immune responses and inflammatory conditions. Furthermore, post-translational modifications such as acetylation and phosphorylation influence HMGB1's secretion.

Passive release of HMGB1 occurs during diverse forms of cell death, including necrosis, necroptosis, apoptosis, NETosis, and others. Regulators include PARP1 in response to DNA damage, RIPK3 in necroptosis, and Cathepsin B from lysosomes. Antioxidant enzymes mitigate oxidative stress, while DNase cleaves nuclear DNA. Caspases in apoptosis, ATG proteins in autophagy, and pH changes also modulate HMGB1 release.

Extracellular HMGB1 Receptors and Signaling Pathways

Extracellular HMGB1 engages several receptors, including RAGE, TLRs (TLR2, TLR4, and TLR9), CXCR4, and TIM-3. RAGE activation by HMGB1 induces NF-κB-mediated inflammation, contributing to autoimmune diseases and cancer progression. TLR2 and TLR4 trigger MyD88-dependent pathways, promoting cytokine production and immune cell activation. TLR9, found intracellularly in endosomes, recognizes HMGB1-DNA complexes, stimulating immune responses against pathogens. CXCR4 activation by HMGB1 regulates cell migration and survival, pivotal in inflammation and cancer metastasis. TIM-3, primarily expressed in T cells, mediates immune suppression upon HMGB1 binding, which is crucial in T cell exhaustion and immune tolerance. These receptors and pathways illustrate HMGB1's dual roles as a DAMP in innate immunity and inflammation, influencing various pathological conditions and immune responses.

Fig.2 The release of HMGB1 protein and HMGB1 signaling pathways.²

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References

1. Chen, Ruochan, Rui Kang, and Daolin Tang. "The mechanism of HMGB1 secretion and release." Experimental & molecular medicine 54.2 (2022): 91-102.
2. Yuan, Shunling, et al. "High mobility group box 1 (HMGB1): a pivotal regulator of hematopoietic malignancies." Journal of Hematology & Oncology 13 (2020): 1-19.