HMGB1 Gene: High Mobility Group Box 1 - Function, Disease Associations, and Clinical Significance
A comprehensive overview of the HMGB1 gene, its protein product, associated diseases, expression patterns, and mutations.
Gene Information Card
| Symbol | HMGB1 |
|---|---|
| Full Name | High Mobility Group Box 1 |
| Gene Type | Protein coding |
| Chromosomal Location | 13q12.3 |
| NCBI Gene ID | 3146 ncbi.nlm.nih.gov/gene/3146 |
| Ensembl ID | ENSG00000189403 |
| UniProt ID | P09429 |
| OMIM ID | 163905 |
| HGNC ID | 4983 |
| Aliases | HMG1, HMG3, SBP-1, HMG-1, DKFZp686A04236 |
Description
The HMGB1 gene encodes the High Mobility Group Box 1 protein, a ubiquitous nuclear protein that plays dual roles: as a DNA-binding protein involved in chromatin structure and transcription regulation, and as an extracellular danger-associated molecular pattern (DAMP) molecule when released from cells. Extracellular HMGB1 triggers inflammatory responses via receptors such as TLR4 and RAGE, contributing to various pathological conditions including sepsis, autoimmune diseases, and cancer.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Sepsis | Extracellular HMGB1 acts as a late mediator of inflammation, sustaining the inflammatory response via TLR4 and RAGE signaling. | Multiple studies (e.g., Wang et al., 1999) show elevated HMGB1 levels in sepsis patients and therapeutic benefit of anti-HMGB1 antibodies in animal models. |
| Rheumatoid Arthritis | HMGB1 is released into the synovial fluid and promotes synovitis by stimulating pro-inflammatory cytokine production from macrophages and synoviocytes. | Clinical studies and animal models demonstrate increased HMGB1 expression in inflamed joints and amelioration of arthritis with HMGB1 blockade. |
| Cancer (various types) | HMGB1 promotes tumor progression through multiple mechanisms: enhancing angiogenesis, metastasis, and immune evasion; also involved in autophagy and chemoresistance. | Overexpression of HMGB1 is observed in many cancers (e.g., breast, lung, colon) and correlates with poor prognosis; functional studies show HMGB1 knockdown reduces tumor growth. |
| Ischemia-Reperfusion Injury | HMGB1 released from necrotic cells during ischemia triggers inflammatory responses and exacerbates tissue damage. | Experimental models of myocardial, cerebral, and hepatic ischemia-reperfusion show that HMGB1 neutralization reduces injury. |
| Alzheimer's Disease | HMGB1 may contribute to neuroinflammation and amyloid-beta aggregation, exacerbating cognitive decline. | Elevated HMGB1 levels in brain and CSF of AD patients; in vitro studies show HMGB1 binds amyloid-beta and promotes its aggregation. |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Lymph node | 82.7 | High |
| Spleen | 78.3 | High |
| Bone marrow | 70.5 | High |
| Appendix | 65.2 | High |
| Lung | 58.4 | High |
| Liver | 45.6 | Medium |
| Kidney | 38.9 | Medium |
| Brain | 25.3 | Low |
| Heart | 20.1 | Low |
| Skeletal muscle | 15.7 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa | 85.2 | Cervical adenocarcinoma; high expression |
| A549 | 72.4 | Lung carcinoma; high expression |
| HepG2 | 68.9 | Hepatocellular carcinoma; high expression |
| MCF7 | 55.3 | Breast adenocarcinoma; moderate expression |
| K562 | 48.7 | Chronic myelogenous leukemia; moderate expression |
| Jurkat | 42.1 | T-cell leukemia; moderate expression |
| SH-SY5Y | 30.5 | Neuroblastoma; low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1A>G (p.Met1Val) | Missense | Rare | Potential loss of function; may affect protein translation initiation. |
| c.3G>A (p.Met1Ile) | Missense | Rare | Potential loss of function; may affect protein translation initiation. |
| c.4C>T (p.Pro2Ser) | Missense | Rare | Uncertain significance; may affect protein stability. |
| c.5C>T (p.Pro2Leu) | Missense | Rare | Uncertain significance; may affect protein stability. |
| c.6C>G (p.Pro2Arg) | Missense | Rare | Uncertain significance; may affect protein stability. |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in HMGB1 are rare and may lead to reduced protein levels or impaired DNA binding, potentially affecting chromatin dynamics and transcriptional regulation. However, complete loss is likely compensated by other HMG family members.
Gain of Function (GOF)
Gain-of-function mutations are not well-documented for HMGB1. Overexpression or increased release of wild-type HMGB1 is more common in disease contexts, leading to enhanced inflammatory signaling.
Dominant Negative (DN)
No dominant-negative mutations have been reported for HMGB1. The protein functions as a monomer, and mutations that disrupt its interactions with DNA or receptors could theoretically act in a dominant-negative manner, but evidence is lacking.
View complete mutation data：
Gene Ontology (GO)
| • DNA binding | • chromatin binding |
| • transcription factor binding | • cytokine activity |
| • chemokine activity | • RAGE receptor binding |
| • TLR4 binding | • nucleus |
| • cytoplasm | • extracellular space |
| • chromosome | • nucleosome |
| • regulation of transcription by RNA polymerase II | • inflammatory response |
| • innate immune response | • cellular response to lipopolysaccharide |
| • apoptotic process | • cell proliferation |
| • angiogenesis | • wound healing |
Pathways
• RAGE signaling pathway
• TLR4 signaling pathway
• NF-kappaB signaling pathway
• MAPK signaling pathway
• p53 signaling pathway
• Apoptosis
• Inflammatory response pathway
• Cytokine-cytokine receptor interaction
Protein Summary
The HMGB1 protein is a 215-amino acid nuclear protein with two DNA-binding domains (HMG boxes A and B) and a C-terminal acidic tail. It binds to DNA without sequence specificity, bending DNA to facilitate transcription, replication, and repair. Upon cellular stress or damage, HMGB1 is actively secreted or passively released from necrotic cells, acting as a DAMP. Extracellular HMGB1 binds to receptors such as TLR4, TLR2, and RAGE, activating signaling cascades that lead to pro-inflammatory cytokine production, chemotaxis, and immune cell activation. HMGB1 also interacts with other molecules like LPS and CXCL12 to modulate immune responses. Its dual nuclear and extracellular roles make it a critical mediator of both homeostasis and pathology.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| Hmgb1 Knockout RAW 264.7 Cell Line | EDJ-KZ285 | Mouse | 15289 | Details Get a Quote |
| HMGB1 Knockout HEK293 Cell Line | EDJ-KQ50350 | Human | 3146 | Details Get a Quote |
| HMGB1 Knockout HeLa Cell Line | EDJ-KQ53529 | Human | 3146 | Details Get a Quote |
| HMGB1 Knockout A-549 Cell Line | EDJ-KQ62002 | Human | 3146 | Details Get a Quote |
| HMGB1 Knockout HCT 116 Cell Line | EDJ-KQ70479 | Human | 3146 | Details Get a Quote |
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