• Engineered LRRK2 kinase-domain inhibitor scaffold 17m ago
  • Huntingtin polyQ-tract recognizer 17m ago
  • TDP-43 N-terminal stabilizer 17m ago
  • α-Synuclein aggregation inhibitor 17m ago
  • Anti-Aβ42 binder de novo 17m ago

HMGB1 — High Mobility Group Box 1

gene

HMGB1 — High Mobility Group Box 1

<table class=“infobox infobox-gene”> <tr> <th class=“infobox-header” colspan=“2”>HMGB1 — High Mobility Group Box 1</th> </tr> <tr> [@santoro2016] <td class=“label”>Symbol</td> [@yang2015] <td><strong>HMGB1</strong></td> [@venereau2012] </tr> [@magna2014] <tr> <td class=“label”>Full Name</td> <td>High Mobility Group Box 1</td> </tr> <tr> <td class=“label”>Chromosome</td> <td>13q12.3</td> </tr> <tr> <td class=“label”>NCBI Gene</td> <td><a href=“https://www.ncbi.nlm.nih.gov/gene/3146” target=“_blank”>3146</a></td> </tr> <tr> <td class=“label”>Ensembl</td> <td><a href=“https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000189403” target=“_blank”>ENSG00000189403</a></td> </tr> <tr> <td class=“label”>OMIM</td> <td><a href=“https://omim.org/entry/163905” target=“_blank”>163905</a></td> </tr> <tr> <td class=“label”>UniProt</td> <td><a href=“https://www.uniprot.org/uniprot/P09429” target=“_blank”>P09429</a></td> </tr> <tr> <td class=“label”>Diseases</td> <td>Alzheimer’s Disease, Parkinson’s Disease, ALS, Stroke, Traumatic Brain Injury</td> </tr> <tr> <td class=“label”>Expression</td> <td>Ubiquitous; enriched in neurons, microglia, astrocytes</td> </tr> <tr> <th class=“infobox-subheader” colspan=“2”>Key Features</th> </tr> <tr> <td colspan=“2” style=“font-size:0.85em”>DAMP (danger signal)<br>TLR4/RAGE ligand<br>Nuclear DNA-binding protein<br>Redox-sensitive alarmin</td> </tr> <tr> <td class=“label”>Associated Diseases</td> <td><a href=“/wiki/als” style=“color:#ef9a9a”>ALS</a>, <a href=“/wiki/alzheimer” style=“color:#ef9a9a”>ALZHEIMER</a>, <a href=“/wiki/alzheimer’s” style=“color:#ef9a9a”>ALZHEIMER’S</a>, <a href=“/wiki/alzheimer’s-disease” style=“color:#ef9a9a”>ALZHEIMER’S DISEASE</a>, <a href=“/wiki/aging” style=“color:#ef9a9a”>Aging</a></td> </tr> <tr> <td class=“label”>KG Connections</td> <td><a href=“/atlas” style=“color:#4fc3f7”>604 edges</a></td> </tr> </table>

HMGB1 — High Mobility Group Box 1

Pathway Diagram

flowchart TD
    HMGB1["HMGB1"]
    style HMGB1 fill:#006494,stroke:#4fc3f7,stroke-width:3px,color:#e0e0e0
    Inflammation["Inflammation"]
    HMGB1 -->|"therapeutic target"| Inflammation
    Apoptosis["Apoptosis"]
    HMGB1 -->|"activates"| Apoptosis
    Als["Als"]
    HMGB1 -->|"activates"| Als
    HMGB1 -->|"inhibits"| Inflammation
    RAGE["RAGE"]
    HMGB1 -->|"activates"| RAGE
    Cognitive_Impairment["Cognitive Impairment"]
    HMGB1 -->|"contributes to"| Cognitive_Impairment
    Oxidative_Stress["Oxidative Stress"]
    HMGB1 -->|"activates"| Oxidative_Stress
    Immune_Response["Immune Response"]
    HMGB1 -->|"activates"| Immune_Response
    Trilobatin["Trilobatin"]
    Trilobatin -->|"targets"| HMGB1
    INFLAMMATION["INFLAMMATION"]
    INFLAMMATION -->|"therapeutic target"| HMGB1
    SIRT3_SOD2_Signaling_Pathway["SIRT3/SOD2 Signaling Pathway"]
    SIRT3_SOD2_Signaling_Pathway -->|"regulates"| HMGB1
    NF__B["NF-KB"]
    NF__B -->|"regulates"| HMGB1
    OXIDATIVE_STRESS["OXIDATIVE STRESS"]
    OXIDATIVE_STRESS -->|"activates"| HMGB1
    OXIDATIVE_STRESS -->|"therapeutic target"| HMGB1
    CYTOKINES["CYTOKINES"]
    CYTOKINES -->|"activates"| HMGB1
    style Inflammation fill:#ef5350,stroke:#ef5350,color:#e0e0e0
    style Apoptosis fill:#5d4400,stroke:#ffd54f,color:#e0e0e0
    style Als fill:#ef5350,stroke:#ef5350,color:#e0e0e0
    style RAGE fill:#4a1a6b,stroke:#ce93d8,color:#e0e0e0
    style Cognitive_Impairment fill:#ef5350,stroke:#ff8a65,color:#e0e0e0
    style Oxidative_Stress fill:#5d4400,stroke:#ffd54f,color:#e0e0e0
    style Immune_Response fill:#5d4400,stroke:#ffd54f,color:#e0e0e0
    style Trilobatin fill:#006494,stroke:#4fc3f7,color:#e0e0e0
    style INFLAMMATION fill:#1b5e20,stroke:#81c784,color:#e0e0e0
    style SIRT3_SOD2_Signaling_Pathway fill:#5d4400,stroke:#ffd54f,color:#e0e0e0
    style NF__B fill:#1b5e20,stroke:#81c784,color:#e0e0e0
    style OXIDATIVE_STRESS fill:#1b5e20,stroke:#81c784,color:#e0e0e0
    style CYTOKINES fill:#1b5e20,stroke:#81c784,color:#e0e0e0

Overview

HMGB1 (High Mobility Group Box 1) is a gene on chromosome 13q12.3 encoding a highly conserved, ubiquitously expressed nuclear protein that functions both as a chromatin architectural factor and as an extracellular danger-associated molecular pattern (DAMP). In the nucleus, HMGB1 bends DNA and facilitates transcription factor binding. When released from damaged or dying neurons, HMGB1 acts as a potent alarmin that activates microglia and astrocytes through TLR4 and RAGE receptors, driving neuroinflammation in Alzheimer’s disease, Parkinson’s disease, ALS, and acute brain injuries.

Key takeaway: HMGB1 is a dual-function protein — chromatin regulator inside the nucleus, potent inflammatory mediator when released extracellularly. Its role as a DAMP makes it a central amplifier of neuroinflammation across neurodegenerative diseases.

Gene Structure and Expression

Genomic Organization

HMGB1 spans approximately 7.5 kb on chromosome 13q12.3, comprising 5 exons. The gene is one of four HMGB family members (HMGB1-4), with HMGB1 being the most abundant and broadly expressed. The gene encodes a 215-amino acid protein with two DNA-binding HMG box domains (A-box and B-box) and an acidic C-terminal tail.

Brain Expression Pattern

HMGB1 is expressed ubiquitously but shows enrichment in:

  • Neurons: High nuclear expression in cortical, hippocampal, and cerebellar neurons
  • Microglia: Expression increases dramatically upon activation; microglia are the primary source of extracellular HMGB1 in the CNS
  • Astrocytes: Moderate expression, with active secretion during reactive astrogliosis
  • Oligodendrocytes: Low basal expression

Expression data is available from the Allen Human Brain Atlas.

Transcriptional Regulation

HMGB1 expression is regulated by:

  • NF-κB: Inflammatory activation increases HMGB1 transcription
  • p53: DNA damage response upregulates HMGB1
  • Interferon regulatory factors: IRF1 and IRF3 regulate HMGB1 in innate immune responses
  • Epigenetic control: Promoter methylation and histone acetylation modulate tissue-specific expression levels

Function

Nuclear Functions

Inside the nucleus, HMGB1 functions as a chromatin architectural protein:

  • DNA bending: HMGB1 binds the minor groove of DNA and induces sharp bends, facilitating nucleosome remodeling and transcription factor access
  • Transcription regulation: Enhances binding of p53, steroid hormone receptors, and NF-κB to their target sequences
  • DNA repair: HMGB1 participates in base excision repair, nucleotide excision repair, and mismatch repair by facilitating access of repair enzymes
  • V(D)J recombination: Required for proper immunoglobulin gene rearrangement
  • Telomere maintenance: HMGB1 associates with telomeric DNA and regulates telomere length

Extracellular Functions (DAMP Activity)

When released extracellularly — passively from necrotic cells or actively secreted by activated immune cells — HMGB1 becomes a potent inflammatory mediator:

  1. RAGE signaling: HMGB1 binds the Receptor for Advanced Glycation End Products, activating NF-κB, MAPK cascades, and pro-inflammatory gene expression
  2. TLR4 activation: Disulfide-HMGB1 signals through TLR4/MD-2 complex, activating MyD88-dependent and TRIF-dependent pathways
  3. TLR2 engagement: HMGB1-nucleosome complexes activate TLR2 signaling
  4. CXCL12 partnership: HMGB1 forms a heterocomplex with the chemokine CXCL12 that signals through CXCR4 to recruit immune cells
  5. NLRP3 inflammasome activation: Extracellular HMGB1 primes and activates the NLRP3 inflammasome, leading to IL-1β and IL-18 release

Redox-Dependent Signaling

HMGB1 activity is critically regulated by its redox state:

  • All-thiol HMGB1 (C23, C45, C106 all reduced): Chemoattractant, promotes cell migration via CXCR4
  • Disulfide HMGB1 (C23-C45 disulfide bond, C106 reduced): Pro-inflammatory cytokine inducer via TLR4
  • Sulfonyl HMGB1 (C106 oxidized to sulfonic acid): Immunologically inactive, promotes resolution of inflammation

This redox switch makes HMGB1 a sensor of the tissue oxidative environment, directly coupling oxidative stress to inflammation.

Disease Associations

Alzheimer’s Disease

HMGB1 plays multiple roles in AD pathogenesis:

  • Amyloid amplification: Extracellular HMGB1 binds amyloid-β oligomers and fibrils, forming HMGB1-Aβ complexes that activate microglia more potently than Aβ alone
  • Neuroinflammation: HMGB1 released from degenerating neurons activates microglial TLR4 and RAGE, sustaining chronic inflammation around amyloid plaques
  • Tau pathology: HMGB1 promotes tau phosphorylation through RAGE-mediated GSK3β activation
  • Blood-brain barrier disruption: HMGB1 increases BBB permeability through endothelial RAGE signaling
  • CSF biomarker: Elevated HMGB1 levels in CSF correlate with disease severity and inflammatory markers

Postmortem studies show increased HMGB1 cytoplasmic translocation and extracellular release in AD hippocampus and cortex compared to age-matched controls.

Parkinson’s Disease

In PD:

  • HMGB1 is released from degenerating dopaminergic neurons in the substantia nigra
  • Activates microglial TLR4 signaling, sustaining dopaminergic neurotoxicity
  • α-Synuclein aggregates trigger HMGB1 release from neurons
  • Anti-HMGB1 antibodies are neuroprotective in MPTP and 6-OHDA PD models
  • HMGB1 levels are elevated in PD patient serum and CSF

ALS

In amyotrophic lateral sclerosis:

  • HMGB1 is released from degenerating motor neurons
  • Activates spinal cord microglia and astrocytes through TLR4 and RAGE
  • Plasma HMGB1 levels correlate with disease progression rate
  • TDP-43 aggregation promotes HMGB1 nuclear-to-cytoplasmic translocation

Stroke and Traumatic Brain Injury

  • Massive HMGB1 release occurs within hours of ischemic injury
  • HMGB1 is one of the earliest DAMPs released after neuronal death
  • Anti-HMGB1 strategies reduce infarct volume in preclinical stroke models

Expression

Developmental and Aging Patterns

Context HMGB1 Level Significance
Embryonic brain Very high (nuclear) Chromatin remodeling, neurogenesis
Adult brain Moderate (nuclear) Transcription regulation
Aging brain Increased cytoplasmic Cellular stress, senescence
AD brain High extracellular Neuroinflammation amplification
Post-injury Massive release DAMP signaling, sterile inflammation

Regulation During Neurodegeneration

HMGB1 undergoes a characteristic nuclear-to-cytoplasmic translocation during neurodegeneration:

  1. Nuclear HMGB1 is hyperacetylated by stress-activated acetyltransferases
  2. Acetylation exposes nuclear export signals, driving cytoplasmic accumulation
  3. Cytoplasmic HMGB1 is actively secreted via lysosomal exocytosis or passively released during necrosis
  4. Extracellular HMGB1 amplifies inflammation through paracrine and autocrine loops

Therapeutic Targeting

Anti-HMGB1 Strategies

  • Anti-HMGB1 monoclonal antibodies: Neutralizing antibodies reduce neuroinflammation in AD, PD, and stroke models
  • BoxA (HMGB1 antagonist): The A-box domain of HMGB1 acts as a competitive antagonist, blocking HMGB1-receptor interactions
  • Glycyrrhizin: Natural compound from licorice root that directly binds HMGB1 and inhibits its extracellular activity; neuroprotective in multiple preclinical models
  • Ethyl pyruvate: Inhibits HMGB1 secretion by activated macrophages/microglia
  • RAGE inhibitors: FPS-ZM1 and other small molecule RAGE antagonists block HMGB1-RAGE signaling
  • TLR4 antagonists: TAK-242 (resatorvid) blocks HMGB1-TLR4 signaling

Clinical Considerations

  • HMGB1 is a validated therapeutic target in multiple inflammatory conditions
  • The redox-dependent activity provides opportunities for selective targeting
  • Combination with anti-amyloid or anti-tau therapies may address both pathology triggers and inflammatory amplification

See Also

External Links

References

  1. Scaffidi et al., Release of chromatin protein HMGB1 by necrotic cells triggers inflammation (2002) (2002)
  2. Yang et al., HMGB1 as a cytokine and therapeutic target (2005) (2005)
  3. Paudel et al., HMGB1: A Common Biomarker and Potential Target for TBI, Neuroinflammation, Epilepsy, and Cognitive Dysfunction (2018) (2018)
  4. Fujita et al., HMGB1, a pathogenic molecule that induces neurite degeneration via TLR4-MARCKS, is a potential therapeutic target for Alzheimer’s disease (2016) (2016)
  5. Santoro et al., In-vivo evidence that high mobility group box 1 exerts deleterious effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model and Parkinson’s disease (2016) (2016)
  6. Yang et al., MD-2 is required for disulfide HMGB1-dependent TLR4 signaling (2015) (2015)
  7. Venereau et al., Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release (2012) (2012)
  8. Unknown, Magna & Bhagavathula, The role of HMGB1 in the pathogenesis of inflammatory and autoimmune diseases (2014) (2014)

Pathway Diagram

The following diagram shows the key molecular relationships involving HMGB1 — High Mobility Group Box 1 discovered through SciDEX knowledge graph analysis:

graph TD
    Trilobatin["Trilobatin"] -->|"targets"| HMGB1["HMGB1"]
    Box_A["Box-A"] -.->|"inhibits"| HMGB1["HMGB1"]
    CXCR7["CXCR7"] -->|"binds"| HMGB1["HMGB1"]
    h_03e31e80["h-03e31e80"] -->|"targets gene"| HMGB1["HMGB1"]
    CNS_Injury["CNS Injury"] -->|"upregulates"| HMGB1["HMGB1"]
    Necrotic_cells["Necrotic cells"] -->|"produces"| HMGB1["HMGB1"]
    INFLAMMATION["INFLAMMATION"] -->|"therapeutic target"| HMGB1["HMGB1"]
    Macrophages["Macrophages"] -->|"produces"| HMGB1["HMGB1"]
    Mycobacterium_vaccae["Mycobacterium vaccae"] -.->|"downregulates"| HMGB1["HMGB1"]
    Glycyrrhizic_Acid["Glycyrrhizic Acid"] -.->|"inhibits"| HMGB1["HMGB1"]
    SIRT3_SOD2_Signaling_Pathway["SIRT3/SOD2 Signaling Pathway"] -->|"regulates"| HMGB1["HMGB1"]
    IL4["IL4"] -.->|"inhibits"| HMGB1["HMGB1"]
    Fungal_Infection["Fungal Infection"] -->|"upregulates"| HMGB1["HMGB1"]
    HSYA["HSYA"] -.->|"downregulates"| HMGB1["HMGB1"]
    Bacterial_Infection["Bacterial Infection"] -->|"upregulates"| HMGB1["HMGB1"]
    style Trilobatin fill:#ff8a65,stroke:#333,color:#000
    style HMGB1 fill:#4fc3f7,stroke:#333,color:#000
    style Box_A fill:#ff8a65,stroke:#333,color:#000
    style CXCR7 fill:#4fc3f7,stroke:#333,color:#000
    style h_03e31e80 fill:#4fc3f7,stroke:#333,color:#000
    style CNS_Injury fill:#ef5350,stroke:#333,color:#000
    style Necrotic_cells fill:#80deea,stroke:#333,color:#000
    style INFLAMMATION fill:#ce93d8,stroke:#333,color:#000
    style Macrophages fill:#80deea,stroke:#333,color:#000
    style Mycobacterium_vaccae fill:#ff8a65,stroke:#333,color:#000
    style Glycyrrhizic_Acid fill:#ff8a65,stroke:#333,color:#000
    style SIRT3_SOD2_Signaling_Pathway fill:#81c784,stroke:#333,color:#000
    style IL4 fill:#4fc3f7,stroke:#333,color:#000
    style Fungal_Infection fill:#ef5350,stroke:#333,color:#000
    style HSYA fill:#ff8a65,stroke:#333,color:#000
    style Bacterial_Infection fill:#ef5350,stroke:#333,color:#000