HMGB1 is a 215-amino acid non-histone chromatin protein containing two HMG-box DNA-binding domains (A-box and B-box) and an acidic C-terminal tail. It has dual functions: (1) Nuclear - binds and bends DNA, modulates chromatin architecture, regulates transcription, and participates in DNA repair (BER, MMR, NER) and V(D)J recombination; (2) Extracellular - acts as a danger-associated molecular pattern (DAMP)/alarmin released from necrotic or activated cells, signaling through TLR4, TLR2, RAGE, and CXCR4 (via CXCL12 heterocomplex). Its activity is redox-regulated: all-thiol HMGB1 is chemotactic, disulfide HMGB1 (C23-C45 bond) induces cytokine production, and fully oxidized HMGB1 is inactive.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0005634
nucleus
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: HMGB1 is predominantly nuclear in basal state and shuttles between nucleus and cytoplasm. UniProt confirms nuclear localization with multiple experimental references.
Reason: Core localization for HMGB1's chromatin-associated functions including DNA binding, transcription regulation, and DNA repair. Well-supported by IDA evidence (PMID:8339930, PMID:19223331).
Supporting Evidence:
UniProt:P09429
Note=In basal state predominantly nuclear
file:human/HMGB1/HMGB1-deep-research-falcon.md
model: Edison Scientific Literature
|
|
GO:0006338
chromatin remodeling
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: HMGB1 modulates chromatin structure by binding DNA, bending it, and facilitating nucleosome dynamics. It can restructure canonical nucleosomes and counteract linker histone H1.
Reason: Core function of HMGB1. The protein binds DNA with preference for non-canonical structures, enhances DNA flexibility, and can displace histone H1 from bent DNA. This represents a fundamental evolved function of the HMGB family.
Supporting Evidence:
UniProt:P09429
Can restructure the canonical nucleosome leading to relaxation of structural constraints for transcription factor-binding (By similarity)
HMGB1-deep-research-falcon.md
HMGB1 deforms nucleosomal DNA and counteracts linker histone H1 suppression of DNA accessibility without displacing H1
|
|
GO:0007165
signal transduction
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: HMGB1 participates in signal transduction when released extracellularly, activating TLR4, TLR2, RAGE, and CXCR4 pathways.
Reason: Extracellular HMGB1 is a bona fide signaling molecule that activates NF-kB, MAPK/ERK, PI3K/AKT pathways through multiple receptors. This is a core extracellular function.
Supporting Evidence:
UniProt:P09429
Disulfide HMGB1 binds to transmembrane receptors, such as AGER/RAGE, TLR2, TLR4 and probably TREM1, thus activating their signal transduction pathways
|
|
GO:0050918
positive chemotaxis
|
IEA
GO_REF:0000108 |
ACCEPT |
Summary: All-thiol (fully reduced) HMGB1 forms a complex with CXCL12 that signals through CXCR4 to promote chemotaxis and inflammatory cell recruitment.
Reason: Core extracellular function of the reduced HMGB1 isoform. The CXCL12-HMGB1 heterocomplex promotes CXCR4-mediated chemotaxis of monocytes and other inflammatory cells.
Supporting Evidence:
UniProt:P09429
Fully reduced HGMB1 (which subsequently gets oxidized after release) in association with CXCL12 mediates the recruitment of inflammatory cells during the initial phase of tissue injury
|
|
GO:0000793
condensed chromosome
|
IEA
GO_REF:0000117 |
ACCEPT |
Summary: HMGB1 associates with mitotic chromosomes, supported by IDA evidence (PMID:12925773).
Reason: HMGB1 is a chromatin-associated protein that remains bound to chromosomes during mitosis. This is consistent with its core role in chromatin architecture.
|
|
GO:0001938
positive regulation of endothelial cell proliferation
|
IEA
GO_REF:0000117 |
KEEP AS NON CORE |
Summary: Extracellular HMGB1 has proangiogenic activity and can stimulate endothelial cell proliferation via RAGE signaling.
Reason: While HMGB1 does have proangiogenic effects, this is a downstream consequence of its alarmin/DAMP signaling function rather than a core evolved function. It represents a pleiotropic effect of extracellular HMGB1.
|
|
GO:0002250
adaptive immune response
|
IEA
GO_REF:0000043 |
KEEP AS NON CORE |
Summary: HMGB1 participates in adaptive immunity by enhancing T cell activation and suppressing regulatory T cells.
Reason: HMGB1 modulates adaptive immunity as a downstream effect of its DAMP/alarmin signaling. This is a pleiotropic consequence rather than a core function.
|
|
GO:0002376
immune system process
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: HMGB1 is involved in both innate and adaptive immune responses as an extracellular alarmin.
Reason: Extracellular HMGB1 signaling through TLR4, TLR2, and RAGE is a core function that activates immune responses. This broad term appropriately captures the immunological role.
|
|
GO:0003677
DNA binding
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: HMGB1 binds DNA through its two HMG-box domains with preference for non-canonical DNA structures.
Reason: DNA binding is the fundamental molecular function of HMGB1. The HMG-box domains bind DNA and bend it, enabling chromatin remodeling and transcription factor access.
|
|
GO:0003684
damaged DNA binding
|
IEA
GO_REF:0000117 |
ACCEPT |
Summary: HMGB1 binds damaged DNA and participates in DNA repair pathways including BER, MMR, and NER.
Reason: Core function. HMGB1 binds cisplatin-modified DNA and other damaged DNA structures, and is a cofactor in base excision repair (PMID:17803946) and mismatch repair (PMID:15014079).
|
|
GO:0003714
transcription corepressor activity
|
IEA
GO_REF:0000117 |
ACCEPT |
Summary: HMGB1 can repress transcription, demonstrated for p53/p73-dependent transactivation (PMID:11748232) and class II genes via TBP interaction (PMID:8006019).
Reason: HMGB1 has documented transcription corepressor activity, shown experimentally in multiple contexts including p53-dependent transcription and MHC class II gene regulation.
|
|
GO:0005576
extracellular region
|
IEA
GO_REF:0000044 |
ACCEPT |
Summary: HMGB1 is released extracellularly from necrotic cells (passively) or activated immune cells (actively) to function as a DAMP/alarmin.
Reason: Core localization for HMGB1's alarmin function. Extracellular release is essential for its signaling through TLR4, RAGE, and CXCR4.
|
|
GO:0005634
nucleus
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: HMGB1 is predominantly nuclear in basal state, functioning as a chromatin-associated protein.
Reason: Core localization. Nucleus is the primary compartment for HMGB1's chromatin-related functions. Duplicate of IBA annotation but valid.
|
|
GO:0005694
chromosome
|
IEA
GO_REF:0000044 |
ACCEPT |
Summary: HMGB1 associates with chromosomes as a chromatin architectural protein.
Reason: HMGB1 is a chromatin-associated protein that binds to chromosomes and modulates their structure. This is consistent with its core nuclear function.
|
|
GO:0005737
cytoplasm
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: HMGB1 translocates to the cytoplasm from the nucleus, especially during autophagy stimulation and prior to secretion.
Reason: Valid localization. HMGB1 shuttles between nucleus and cytoplasm, and cytoplasmic localization is important for its secretion pathway and autophagy-related functions.
|
|
GO:0005768
endosome
|
IEA
GO_REF:0000044 |
ACCEPT |
Summary: HMGB1 localizes to endosomes, involved in TLR9 activation and nucleic acid sensing.
Reason: HMGB1 is involved in endosomal translocation and activation of TLR9 in response to CpG-DNA. Endosomal localization is part of its immune sensing function.
|
|
GO:0005783
endoplasmic reticulum
|
IEA
GO_REF:0000044 |
ACCEPT |
Summary: HMGB1 localizes to ER, particularly during SARS-CoV-2 infection where ORF3a promotes its translocation there.
Reason: Valid localization supported by IDA evidence (PMID:35239449). ER localization is part of HMGB1's secretory pathway and its role in ER stress responses.
|
|
GO:0005793
endoplasmic reticulum-Golgi intermediate compartment
|
IEA
GO_REF:0000044 |
ACCEPT |
Summary: HMGB1 localizes to ERGIC as part of its non-classical secretory pathway.
Reason: HMGB1 is secreted via a non-classical pathway involving secretory lysosomes. ERGIC localization is consistent with this secretory mechanism.
|
|
GO:0005886
plasma membrane
|
IEA
GO_REF:0000044 |
ACCEPT |
Summary: HMGB1 is found on the surface of activated platelets and can associate with cell membrane.
Reason: HMGB1 is found on the surface of activated platelets (PMID:11154118). Peripheral membrane association is documented.
|
|
GO:0006259
DNA metabolic process
|
IEA
GO_REF:0000117 |
ACCEPT |
Summary: HMGB1 participates in DNA metabolism through its roles in replication, repair, and recombination.
Reason: Broad term that appropriately captures HMGB1's involvement in DNA replication, repair (BER, MMR, NER), and V(D)J recombination.
|
|
GO:0006281
DNA repair
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: HMGB1 is a cofactor in multiple DNA repair pathways including BER, MMR, and NER.
Reason: Core nuclear function. HMGB1 is a cofactor in mammalian base excision repair (PMID:17803946), mismatch repair (PMID:15014079), and facilitates nucleotide excision repair (PMID:19446504).
|
|
GO:0006310
DNA recombination
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: HMGB1 is involved in V(D)J recombination as a cofactor of the RAG complex.
Reason: Core function. HMGB1 stimulates RAG cleavage activity and is involved in V(D)J recombination (PMID:9166431).
|
|
GO:0006914
autophagy
|
IEA
GO_REF:0000043 |
MARK AS OVER ANNOTATED |
Summary: Cytoplasmic HMGB1 promotes autophagy by binding Beclin-1 and displacing BCL2, but this is a secondary function.
Reason: While HMGB1 can promote autophagy via Beclin-1 interaction (PMID:20819940), this is a secondary/pleiotropic function, not its evolved core function. The core functions are chromatin biology (nuclear) and alarmin signaling (extracellular).
|
|
GO:0006935
chemotaxis
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: All-thiol HMGB1 in complex with CXCL12 promotes chemotaxis of inflammatory cells via CXCR4.
Reason: Core extracellular function. The HMGB1-CXCL12 heterocomplex signals through CXCR4 to promote chemotaxis of monocytes and other inflammatory cells (PMID:22370717).
|
|
GO:0006954
inflammatory response
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: Extracellular HMGB1 is a prototypical alarmin that promotes inflammatory responses through TLR4, TLR2, and RAGE.
Reason: Core extracellular function. Disulfide HMGB1 induces cytokine release (TNF, IL-1, IL-6, IL-8) through receptor activation (PMID:12765338).
|
|
GO:0006955
immune response
|
IEA
GO_REF:0000117 |
ACCEPT |
Summary: HMGB1 participates in both innate and adaptive immune responses as a DAMP molecule.
Reason: Core function. HMGB1 is a danger-associated molecular pattern (DAMP) that amplifies immune responses during tissue injury.
|
|
GO:0006974
DNA damage response
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: HMGB1 participates in DNA damage response as a cofactor in multiple repair pathways.
Reason: Core nuclear function. HMGB1 binds damaged DNA and participates in BER, MMR, and NER pathways.
|
|
GO:0008289
lipid binding
|
IEA
GO_REF:0000117 |
ACCEPT |
Summary: HMGB1 binds phosphatidylserine and phosphatidylethanolamine on cell surfaces.
Reason: HMGB1 binds phosphatidylserine on apoptotic cells and inhibits their phagocytosis (PMID:18768881). This is part of its immunomodulatory function.
|
|
GO:0010596
negative regulation of endothelial cell migration
|
IEA
GO_REF:0000117 |
KEEP AS NON CORE |
Summary: HMGB1 can negatively regulate endothelial cell migration through TLR4 and IRF3.
Reason: While HMGB1 can inhibit endothelial migration (PMID:23148224), this is a context-dependent pleiotropic effect rather than a core function.
|
|
GO:0032722
positive regulation of chemokine production
|
IEA
GO_REF:0000117 |
ACCEPT |
Summary: Extracellular HMGB1 stimulates production of chemokines like CCL2, CCL3, CCL4, and CXCL10.
Reason: Core alarmin function. HMGB1 signaling through TLR4 and RAGE induces chemokine production as part of inflammatory response.
|
|
GO:0032732
positive regulation of interleukin-1 production
|
IEA
GO_REF:0000117 |
ACCEPT |
Summary: HMGB1 stimulates IL-1 production via TLR4 signaling.
Reason: Core alarmin function. HMGB1 induces IL-1 production through receptor activation (PMID:12765338).
|
|
GO:0045087
innate immune response
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: HMGB1 is a key mediator of innate immune responses as a DAMP/alarmin.
Reason: Core extracellular function. HMGB1 activates innate immune cells through TLR4, TLR2, TLR9, and RAGE signaling.
|
|
GO:0045597
positive regulation of cell differentiation
|
IEA
GO_REF:0000117 |
KEEP AS NON CORE |
Summary: HMGB1 can promote cell differentiation including dendritic cell differentiation.
Reason: While HMGB1 promotes dendritic cell differentiation (PMID:15944249), this is a downstream pleiotropic effect of its alarmin signaling rather than a core function.
|
|
GO:0048018
receptor ligand activity
|
IEA
GO_REF:0000117 |
ACCEPT |
Summary: Extracellular HMGB1 acts as a ligand for multiple receptors including TLR4, TLR2, RAGE, and CXCR4.
Reason: Core molecular function. HMGB1 is a bona fide receptor ligand that binds and activates TLR4, TLR2, RAGE, and works with CXCL12 to signal through CXCR4.
|
|
GO:0048468
cell development
|
IEA
GO_REF:0000117 |
KEEP AS NON CORE |
Summary: HMGB1 may influence cell development through its chromatin and signaling functions.
Reason: This is a broad term capturing downstream effects. HMGB1 influences development through its transcriptional regulatory roles, but this is not a core evolved function.
|
|
GO:0050792
regulation of viral process
|
IEA
GO_REF:0000117 |
ACCEPT |
Summary: HMGB1 regulates viral processes including SARS-CoV-2, influenza, dengue, and EBV infection.
Reason: HMGB1 is critical for coronavirus entry (PMID:33147444), promotes influenza replication (PMID:22696656), and facilitates dengue virus propagation (PMID:34971702).
|
|
GO:0051052
regulation of DNA metabolic process
|
IEA
GO_REF:0000117 |
ACCEPT |
Summary: HMGB1 regulates DNA metabolism through its roles in repair, replication, and recombination.
Reason: Core function. HMGB1 is a DNA chaperone that regulates DNA repair, replication, and recombination.
|
|
GO:1903706
regulation of hemopoiesis
|
IEA
GO_REF:0000117 |
KEEP AS NON CORE |
Summary: HMGB1 may regulate hematopoiesis through its immune signaling functions.
Reason: This is a downstream pleiotropic effect of HMGB1's alarmin signaling rather than a core evolved function.
|
|
GO:0005515
protein binding
|
IPI
PMID:15014079 Evidence for involvement of HMGB1 protein in human DNA misma... |
MODIFY |
Summary: HMGB1 interacts with MSH2 in DNA mismatch repair.
Reason: Protein binding is too vague. The interaction with MSH2 is functionally relevant to DNA repair.
Proposed replacements:
protein-containing complex binding
Supporting Evidence:
PMID:15014079
2004 Mar 9. Evidence for involvement of HMGB1 protein in human DNA mismatch repair.
|
|
GO:0005515
protein binding
|
IPI
PMID:20819940 Endogenous HMGB1 regulates autophagy. |
MODIFY |
Summary: HMGB1 interacts with Beclin-1 in autophagy regulation.
Reason: Protein binding is too vague. The interaction with BECN1 is specific and functionally relevant.
Proposed replacements:
protein-containing complex binding
Supporting Evidence:
PMID:20819940
Endogenous HMGB1 regulates autophagy.
|
|
GO:0005515
protein binding
|
IPI
PMID:23063560 HMGB1-facilitated p53 DNA binding occurs via HMG-Box/p53 tra... |
MODIFY |
Summary: HMGB1 interacts with p53 to facilitate p53-DNA binding.
Reason: Protein binding is too vague. Interaction with p53 is functionally important for transcription regulation.
Proposed replacements:
protein-containing complex binding
Supporting Evidence:
PMID:23063560
2012 Oct 11. HMGB1-facilitated p53 DNA binding occurs via HMG-Box/p53 transactivation domain interaction, regulated by the acidic tail.
|
|
GO:0005515
protein binding
|
IPI
PMID:23303669 Chaperone-like activity of high-mobility group box 1 protein... |
MODIFY |
Summary: HMGB1 interacts with huntingtin (HTT) and has chaperone-like activity reducing polyQ aggregates.
Reason: Protein binding is too vague. More informative terms would capture the chaperone-like function.
Proposed replacements:
unfolded protein binding
Supporting Evidence:
PMID:23303669
2013 Jan 9. Chaperone-like activity of high-mobility group box 1 protein and its role in reducing the formation of polyglutamine aggregates.
|
|
GO:0005515
protein binding
|
IPI
PMID:24474694 An immunogenic peptide in the A-box of HMGB1 protein reverse... |
MODIFY |
Summary: HMGB1 interacts with RAGE receptor.
Reason: Protein binding is too vague. RAGE binding is core to HMGB1 alarmin function.
Proposed replacements:
RAGE receptor binding
Supporting Evidence:
PMID:24474694
2014 Jan 28. An immunogenic peptide in the A-box of HMGB1 protein reverses apoptosis-induced tolerance through RAGE receptor.
|
|
GO:0005515
protein binding
|
IPI
PMID:25416956 A proteome-scale map of the human interactome network. |
ACCEPT |
Summary: High-throughput interactome study identifying HMGB1 interactions.
Reason: High-throughput interactome data provides valid evidence for protein binding capacity.
Supporting Evidence:
PMID:25416956
A proteome-scale map of the human interactome network.
|
|
GO:0005515
protein binding
|
IPI
PMID:28514442 Architecture of the human interactome defines protein commun... |
ACCEPT |
Summary: High-throughput interactome mapping.
Reason: High-throughput interactome data provides valid evidence for protein binding capacity.
Supporting Evidence:
PMID:28514442
Architecture of the human interactome defines protein communities and disease networks.
|
|
GO:0005515
protein binding
|
IPI
PMID:29721183 Delineating the HMGB1 and HMGB2 interactome in prostate and ... |
ACCEPT |
Summary: HMGB1/HMGB2 interactome in prostate and ovary cells.
Reason: Interactome study provides valid evidence for protein binding.
Supporting Evidence:
PMID:29721183
eCollection 2018 Apr 10.
|
|
GO:0005515
protein binding
|
IPI
PMID:31694235 Characterization of HMGB1/2 Interactome in Prostate Cancer b... |
ACCEPT |
Summary: HMGB1/2 interactome characterization by yeast two-hybrid.
Reason: Valid experimental evidence for protein binding capacity.
Supporting Evidence:
PMID:31694235
Characterization of HMGB1/2 Interactome in Prostate Cancer by Yeast Two Hybrid Approach: Potential Pathobiological Implications.
|
|
GO:0005515
protein binding
|
IPI
PMID:32296183 A reference map of the human binary protein interactome. |
ACCEPT |
Summary: Binary protein interactome reference map.
Reason: High-throughput interactome data provides valid evidence for protein binding.
Supporting Evidence:
PMID:32296183
Apr 8. A reference map of the human binary protein interactome.
|
|
GO:0005515
protein binding
|
IPI
PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... |
ACCEPT |
Summary: Interactome mapping of neurodegenerative disease proteins.
Reason: Valid interactome evidence.
Supporting Evidence:
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
|
|
GO:0005515
protein binding
|
IPI
PMID:32867128 The HMGB1-2 Ovarian Cancer Interactome. The Role of HMGB Pro... |
ACCEPT |
Summary: HMGB1-2 ovarian cancer interactome.
Reason: Valid interactome evidence.
Supporting Evidence:
PMID:32867128
The HMGB1-2 Ovarian Cancer Interactome.
|
|
GO:0005515
protein binding
|
IPI
PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... |
ACCEPT |
Summary: Dual proteome-scale networks.
Reason: High-throughput interactome data provides valid evidence for protein binding.
Supporting Evidence:
PMID:33961781
2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
|
|
GO:0005515
protein binding
|
IPI
PMID:40205054 Multimodal cell maps as a foundation for structural and func... |
ACCEPT |
Summary: Multimodal cell maps interactome.
Reason: High-throughput interactome data.
Supporting Evidence:
PMID:40205054
Apr 9. Multimodal cell maps as a foundation for structural and functional genomics.
|
|
GO:0005515
protein binding
|
IPI
PMID:9472015 High mobility group protein-1 (HMG-1) is a unique activator ... |
MODIFY |
Summary: HMGB1 is a unique activator of p53 through direct interaction.
Reason: Protein binding is too vague. The p53 interaction is functionally important.
Proposed replacements:
p53 binding
Supporting Evidence:
PMID:9472015
High mobility group protein-1 (HMG-1) is a unique activator of p53.
|
|
GO:0001773
myeloid dendritic cell activation
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: HMGB1 activates dendritic cells through RAGE signaling.
Reason: Downstream effect of HMGB1's alarmin signaling. DC activation is a consequence of receptor engagement, not a core function.
|
|
GO:0001935
endothelial cell proliferation
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: HMGB1 has proangiogenic activity affecting endothelial cells.
Reason: Pleiotropic effect of HMGB1 signaling through RAGE. Not a core evolved function.
|
|
GO:0002270
plasmacytoid dendritic cell activation
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: HMGB1 activates plasmacytoid dendritic cells, particularly with CpG-DNA.
Reason: Downstream effect of HMGB1's immune signaling function.
|
|
GO:0002281
macrophage activation involved in immune response
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: HMGB1 activates macrophages through TLR4 signaling.
Reason: Macrophage activation is a direct and well-documented effect of HMGB1 signaling through TLR4.
|
|
GO:0002643
regulation of tolerance induction
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Oxidized HMGB1 from apoptotic cells promotes immunological tolerance.
Reason: Sulfonyl HMGB1 from apoptotic cells promotes tolerance (PMID:18631454). This is part of HMGB1's redox-regulated immunomodulatory function.
|
|
GO:0002840
regulation of T cell mediated immune response to tumor cell
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: HMGB1 regulates T cell responses to tumors.
Reason: Pleiotropic effect of HMGB1's immune signaling. Context-dependent and not a core function.
|
|
GO:0003690
double-stranded DNA binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: HMGB1 binds double-stranded DNA through its HMG-box domains.
Reason: Core molecular function. The HMG-box domains bind dsDNA with preference for bent or distorted structures.
|
|
GO:0003725
double-stranded RNA binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: HMGB1 can bind double-stranded RNA.
Reason: HMGB1 is proposed as a universal biosensor for nucleic acids, including RNA. HDA evidence supports RNA binding (PMID:22658674, PMID:22681889).
|
|
GO:0003727
single-stranded RNA binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: HMGB1 can bind single-stranded RNA as part of its nucleic acid sensing function.
Reason: HMGB1 binds various nucleic acids including ssRNA. HDA evidence supports RNA binding (PMID:22658674, PMID:22681889).
|
|
GO:0005125
cytokine activity
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Disulfide HMGB1 acts as a cytokine, inducing production of inflammatory mediators.
Reason: Core extracellular function. Disulfide HMGB1 has cytokine-like activity, inducing TNF, IL-1, IL-6 release from immune cells.
|
|
GO:0005615
extracellular space
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: HMGB1 is released into extracellular space from necrotic or activated cells.
Reason: Core localization for alarmin function. Extensively documented with IDA evidence (PMID:19841752, PMID:25595774).
|
|
GO:0005769
early endosome
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: HMGB1 localizes to early endosomes as part of its TLR9 activation pathway.
Reason: HMGB1 is involved in endosomal translocation and activation of TLR9. Valid localization.
|
|
GO:0006284
base-excision repair
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: HMGB1 is a cofactor in mammalian base excision repair.
Reason: Core nuclear function. HMGB1 is a cofactor in BER, interacting with POLB, FEN1, and APE1 (PMID:17803946).
|
|
GO:0006325
chromatin organization
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: HMGB1 is a chromatin architectural protein that modulates chromatin structure.
Reason: Core nuclear function. HMGB1 binds DNA, bends it, and facilitates nucleosome dynamics.
|
|
GO:0010508
positive regulation of autophagy
|
IEA
GO_REF:0000120 |
MARK AS OVER ANNOTATED |
Summary: Cytoplasmic HMGB1 promotes autophagy through Beclin-1 interaction.
Reason: While HMGB1 can promote autophagy via Beclin-1 (PMID:20819940), this is a secondary/pleiotropic function, not its evolved core function.
|
|
GO:0010858
calcium-dependent protein kinase regulator activity
|
IEA
GO_REF:0000107 |
UNDECIDED |
Summary: Evidence for HMGB1 regulating calcium-dependent protein kinases is limited.
Reason: Limited direct evidence for this specific activity. Requires further investigation.
|
|
GO:0030295
protein kinase activator activity
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: HMGB1 activates kinase cascades (MAPK, ERK, JNK) through receptor signaling.
Reason: Kinase activation is an indirect downstream effect of HMGB1 receptor signaling, not a direct molecular function.
|
|
GO:0032727
positive regulation of interferon-alpha production
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: HMGB1 promotes IFN-alpha production through TLR9 activation in plasmacytoid DCs.
Reason: Part of HMGB1's innate immune signaling function. HMGB1 with CpG-DNA activates TLR9-mediated interferon production.
|
|
GO:0032728
positive regulation of interferon-beta production
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: HMGB1 promotes IFN-beta production through innate immune signaling.
Reason: Part of HMGB1's innate immune function via TLR signaling.
|
|
GO:0032731
positive regulation of interleukin-1 beta production
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: HMGB1 induces IL-1beta production through TLR4 and inflammasome activation.
Reason: Core alarmin function. Disulfide HMGB1 induces IL-1beta production through TLR4 signaling and inflammasome priming.
|
|
GO:0032755
positive regulation of interleukin-6 production
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: HMGB1 induces IL-6 production from immune cells.
Reason: Core alarmin function. Well-documented cytokine induction by HMGB1 (PMID:12765338, PMID:26961863).
|
|
GO:0032760
positive regulation of tumor necrosis factor production
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: HMGB1 induces TNF production through TLR4 signaling.
Reason: Core alarmin function. TNF induction is a well-documented effect of HMGB1 (PMID:12765338).
|
|
GO:0034137
positive regulation of toll-like receptor 2 signaling pathway
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: HMGB1 activates TLR2 signaling, especially with lipoteichoic acid.
Reason: Core alarmin function. HMGB1 binds lipoteichoic acid and transfers it to CD14 for TLR2 signaling.
|
|
GO:0034145
positive regulation of toll-like receptor 4 signaling pathway
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Disulfide HMGB1 binds TLR4-MD2 and activates signaling.
Reason: Core alarmin function. TLR4 is the primary receptor for disulfide HMGB1's cytokine-inducing activity (PMID:20547845).
|
|
GO:0035767
endothelial cell chemotaxis
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: HMGB1 promotes endothelial cell chemotaxis as part of its proangiogenic activity.
Reason: Downstream pleiotropic effect of HMGB1's alarmin/RAGE signaling.
|
|
GO:0043005
neuron projection
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: HMGB1 localizes to neuron projections and promotes neuronal outgrowth via RAGE.
Reason: Neuronal localization and outgrowth promotion is a tissue-specific pleiotropic effect.
|
|
GO:0045089
positive regulation of innate immune response
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: HMGB1 is a key activator of innate immune responses through multiple TLRs and RAGE.
Reason: Core extracellular function. HMGB1 is a prototypical DAMP that activates innate immunity.
|
|
GO:0070374
positive regulation of ERK1 and ERK2 cascade
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: HMGB1 activates ERK1/2 signaling through RAGE and TLR4.
Reason: Well-documented downstream signaling of HMGB1-receptor activation.
|
|
GO:0071222
cellular response to lipopolysaccharide
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: HMGB1 binds LPS and enhances LPS-mediated cellular responses.
Reason: HMGB1 binds LPS and transfers it to CD14 for TLR4 signaling (PMID:18354232, PMID:21660935).
|
|
GO:0071639
positive regulation of monocyte chemotactic protein-1 production
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: HMGB1 induces MCP-1/CCL2 production.
Reason: Part of HMGB1's chemokine-inducing activity.
|
|
GO:0090303
positive regulation of wound healing
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: HMGB1 promotes wound healing through its proangiogenic and immune-modulatory effects.
Reason: Wound healing promotion is a downstream pleiotropic effect of HMGB1's alarmin signaling.
|
|
GO:1901224
positive regulation of non-canonical NF-kappaB signal transduction
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: HMGB1 activates NF-kappaB signaling through RAGE and TLR4.
Reason: NF-kappaB activation is a well-documented downstream effect of HMGB1 receptor signaling.
|
|
GO:1903672
positive regulation of sprouting angiogenesis
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: HMGB1 has proangiogenic activity promoting sprouting angiogenesis.
Reason: Angiogenesis promotion is a downstream pleiotropic effect of HMGB1's RAGE signaling.
|
|
GO:2000819
regulation of nucleotide-excision repair
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: HMGB1 may facilitate nucleotide excision repair through interaction with XPA and XPC.
Reason: HMGB1 interacts with XPA and XPC to facilitate NER (PMID:19446504).
|
|
GO:0005654
nucleoplasm
|
IDA
GO_REF:0000052 |
ACCEPT |
Summary: HMGB1 localizes to nucleoplasm as a chromatin-associated protein.
Reason: Valid localization. HMGB1 is predominantly nuclear.
|
|
GO:0140656
endodeoxyribonuclease activator activity
|
IDA
PMID:17803946 HMGB1 is a cofactor in mammalian base excision repair. |
ACCEPT |
Summary: HMGB1 activates FEN1 endonuclease activity in base excision repair.
Reason: Core function in DNA repair. HMGB1 stimulates FEN1 endonuclease activity as part of BER (PMID:17803946).
Supporting Evidence:
PMID:17803946
HMGB1 is a cofactor in mammalian base excision repair.
|
|
GO:0006302
double-strand break repair
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: HMGB1 participates in double-strand break repair including NHEJ and V(D)J recombination.
Reason: Core nuclear function. Supported by sequence similarity to characterized orthologs.
|
|
GO:0005515
protein binding
|
IPI
PMID:35239449 SARS-CoV-2 ORF3a induces RETREG1/FAM134B-dependent reticulop... |
ACCEPT |
Summary: HMGB1 interacts with SARS-CoV-2 ORF3A protein.
Reason: Valid experimental evidence for protein interaction with viral protein.
Supporting Evidence:
PMID:35239449
2022 Mar 3. SARS-CoV-2 ORF3a induces RETREG1/FAM134B-dependent reticulophagy and triggers sequential ER stress and inflammatory responses during SARS-CoV-2 infection.
|
|
GO:0005783
endoplasmic reticulum
|
IDA
PMID:35239449 SARS-CoV-2 ORF3a induces RETREG1/FAM134B-dependent reticulop... |
ACCEPT |
Summary: HMGB1 localizes to ER during SARS-CoV-2 infection.
Reason: Valid IDA evidence for ER localization during viral infection.
Supporting Evidence:
PMID:35239449
2022 Mar 3. SARS-CoV-2 ORF3a induces RETREG1/FAM134B-dependent reticulophagy and triggers sequential ER stress and inflammatory responses during SARS-CoV-2 infection.
|
|
GO:0046598
positive regulation of viral entry into host cell
|
IMP
PMID:33147444 Genome-wide CRISPR Screens Reveal Host Factors Critical for ... |
ACCEPT |
Summary: HMGB1 is critical for SARS-CoV-2 and other coronavirus entry.
Reason: HMGB1 regulates expression of ACE2 and CTSL, promoting coronavirus entry (PMID:33147444).
Supporting Evidence:
PMID:33147444
Oct 20. Genome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 Infection.
|
|
GO:0005515
protein binding
|
IPI
PMID:15379539 The long acidic tail of high mobility group box 1 (HMGB1) pr... |
ACCEPT |
Summary: HMGB1 interacts with various proteins in a high-throughput study.
Reason: Valid high-throughput interactome evidence.
Supporting Evidence:
PMID:15379539
The long acidic tail of high mobility group box 1 (HMGB1) protein forms an extended and flexible structure that interacts with specific residues within and between the HMG boxes.
|
|
GO:0031507
heterochromatin formation
|
IGI
PMID:19158276 Chromatin-specific remodeling by HMGB1 and linker histone H1... |
KEEP AS NON CORE |
Summary: HMGB1 may be involved in heterochromatin formation.
Reason: Chromatin-related function but not a core activity. May be secondary to general chromatin architectural role.
Supporting Evidence:
PMID:19158276
Jan 21. Chromatin-specific remodeling by HMGB1 and linker histone H1 silences proinflammatory genes during endotoxin tolerance.
|
|
GO:0000122
negative regulation of transcription by RNA polymerase II
|
IDA
PMID:11748232 HMGB1 and HMGB2 cell-specifically down-regulate the p53- and... |
ACCEPT |
Summary: HMGB1 represses p53/p73-dependent transactivation of Bax and p21 promoters.
Reason: Core transcription regulatory function. HMGB1 can repress transcription as demonstrated for p53/p73-dependent genes (PMID:11748232).
Supporting Evidence:
PMID:11748232
Dec 17. HMGB1 and HMGB2 cell-specifically down-regulate the p53- and p73-dependent sequence-specific transactivation from the human Bax gene promoter.
|
|
GO:0003714
transcription corepressor activity
|
IDA
PMID:11748232 HMGB1 and HMGB2 cell-specifically down-regulate the p53- and... |
ACCEPT |
Summary: HMGB1 has transcription corepressor activity inhibiting p53/p73 transactivation.
Reason: Valid IDA evidence. HMGB1 acts as a corepressor for p53/p73-dependent transcription (PMID:11748232).
Supporting Evidence:
PMID:11748232
Dec 17. HMGB1 and HMGB2 cell-specifically down-regulate the p53- and p73-dependent sequence-specific transactivation from the human Bax gene promoter.
|
|
GO:0061629
RNA polymerase II-specific DNA-binding transcription factor binding
|
IPI
PMID:19223331 HMGB1 and HMGB2 proteins up-regulate cellular expression of ... |
ACCEPT |
Summary: HMGB1 binds transcription factors to facilitate their DNA binding.
Reason: Core function. HMGB1 interacts with and enhances binding of various transcription factors including p53, SREBPs, and others.
Supporting Evidence:
PMID:19223331
Feb 17. HMGB1 and HMGB2 proteins up-regulate cellular expression of human topoisomerase IIalpha.
|
|
GO:0005615
extracellular space
|
IDA
PMID:25595774 Cutting Edge: identification of neutrophil PGLYRP1 as a liga... |
ACCEPT |
Summary: HMGB1 is released to extracellular space as an alarmin.
Reason: Core localization for HMGB1's DAMP function. Well-documented extracellular release.
Supporting Evidence:
PMID:25595774
2015 Jan 16. Cutting Edge: identification of neutrophil PGLYRP1 as a ligand for TREM-1.
|
|
GO:0048018
receptor ligand activity
|
IDA
PMID:17568691 Endogenous signals released from necrotic cells augment infl... |
ACCEPT |
Summary: HMGB1 acts as a ligand for TLR4, TLR2, RAGE receptors.
Reason: Core molecular function. HMGB1 is a bona fide receptor ligand for multiple immune receptors (PMID:17568691).
Supporting Evidence:
PMID:17568691
2007 May 25. Endogenous signals released from necrotic cells augment inflammatory responses to bacterial endotoxin.
|
|
GO:0006303
double-strand break repair via nonhomologous end joining
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: HMGB1 participates in NHEJ DNA repair.
Reason: Core nuclear function supported by sequence similarity.
|
|
GO:0010508
positive regulation of autophagy
|
IMP
PMID:20819940 Endogenous HMGB1 regulates autophagy. |
MARK AS OVER ANNOTATED |
Summary: HMGB1 promotes autophagy through Beclin-1 interaction.
Reason: While HMGB1 can promote autophagy via Beclin-1 (PMID:20819940), this is a secondary/pleiotropic function, not a core evolved function. Core functions are chromatin biology and alarmin signaling.
Supporting Evidence:
PMID:20819940
Endogenous HMGB1 regulates autophagy.
|
|
GO:0003713
transcription coactivator activity
|
IDA
PMID:19223331 HMGB1 and HMGB2 proteins up-regulate cellular expression of ... |
ACCEPT |
Summary: HMGB1 has transcription coactivator activity enhancing transcription factor binding.
Reason: Core nuclear function. HMGB1 enhances binding and activity of various transcription factors (PMID:19223331).
Supporting Evidence:
PMID:19223331
Feb 17. HMGB1 and HMGB2 proteins up-regulate cellular expression of human topoisomerase IIalpha.
|
|
GO:0005615
extracellular space
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: HMGB1 is released to extracellular space.
Reason: Core localization for alarmin function. Supported by sequence similarity.
|
|
GO:0005634
nucleus
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: HMGB1 localizes to nucleus.
Reason: Core localization. Supported by sequence similarity to characterized orthologs.
|
|
GO:0071222
cellular response to lipopolysaccharide
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: HMGB1 mediates cellular response to LPS.
Reason: HMGB1 binds LPS and enhances TLR4-mediated responses. Supported by ISS.
|
|
GO:0000122
negative regulation of transcription by RNA polymerase II
|
IMP
PMID:19158276 Chromatin-specific remodeling by HMGB1 and linker histone H1... |
ACCEPT |
Summary: HMGB1 represses transcription in specific contexts.
Reason: Valid IMP evidence for transcription repression function.
Supporting Evidence:
PMID:19158276
Jan 21. Chromatin-specific remodeling by HMGB1 and linker histone H1 silences proinflammatory genes during endotoxin tolerance.
|
|
GO:0000122
negative regulation of transcription by RNA polymerase II
|
IGI
PMID:19158276 Chromatin-specific remodeling by HMGB1 and linker histone H1... |
ACCEPT |
Summary: HMGB1 involved in transcription repression.
Reason: Valid IGI evidence supporting transcription regulatory function.
Supporting Evidence:
PMID:19158276
Jan 21. Chromatin-specific remodeling by HMGB1 and linker histone H1 silences proinflammatory genes during endotoxin tolerance.
|
|
GO:0000976
transcription cis-regulatory region binding
|
IDA
PMID:19158276 Chromatin-specific remodeling by HMGB1 and linker histone H1... |
ACCEPT |
Summary: HMGB1 binds cis-regulatory regions of DNA.
Reason: Core function. HMGB1 binds DNA including regulatory regions to modulate transcription.
Supporting Evidence:
PMID:19158276
Jan 21. Chromatin-specific remodeling by HMGB1 and linker histone H1 silences proinflammatory genes during endotoxin tolerance.
|
|
GO:0017053
transcription repressor complex
|
IDA
PMID:19158276 Chromatin-specific remodeling by HMGB1 and linker histone H1... |
ACCEPT |
Summary: HMGB1 is part of transcription repressor complexes.
Reason: Valid IDA evidence. HMGB1 can participate in transcription repressor complexes.
Supporting Evidence:
PMID:19158276
Jan 21. Chromatin-specific remodeling by HMGB1 and linker histone H1 silences proinflammatory genes during endotoxin tolerance.
|
|
GO:0043536
positive regulation of blood vessel endothelial cell migration
|
IMP
PMID:28276476 miR-193a-3p interaction with HMGB1 downregulates human endot... |
KEEP AS NON CORE |
Summary: HMGB1 promotes endothelial cell migration as part of proangiogenic activity.
Reason: Downstream pleiotropic effect of HMGB1's RAGE signaling.
Supporting Evidence:
PMID:28276476
miR-193a-3p interaction with HMGB1 downregulates human endothelial cell proliferation and migration.
|
|
GO:1905564
positive regulation of vascular endothelial cell proliferation
|
IMP
PMID:28276476 miR-193a-3p interaction with HMGB1 downregulates human endot... |
KEEP AS NON CORE |
Summary: HMGB1 promotes vascular endothelial cell proliferation.
Reason: Downstream pleiotropic effect of HMGB1's proangiogenic signaling through RAGE.
Supporting Evidence:
PMID:28276476
miR-193a-3p interaction with HMGB1 downregulates human endothelial cell proliferation and migration.
|
|
GO:0005178
integrin binding
|
IDA
PMID:20826760 HMGB1 inhibits macrophage activity in efferocytosis through ... |
ACCEPT |
Summary: HMGB1 binds alphav-beta3 integrin.
Reason: Valid IDA evidence. Integrin binding is part of HMGB1's extracellular signaling repertoire.
Supporting Evidence:
PMID:20826760
HMGB1 inhibits macrophage activity in efferocytosis through binding to the alphavbeta3-integrin.
|
|
GO:0035868
alphav-beta3 integrin-HMGB1 complex
|
IDA
PMID:20826760 HMGB1 inhibits macrophage activity in efferocytosis through ... |
ACCEPT |
Summary: HMGB1 forms complex with alphav-beta3 integrin.
Reason: Valid IDA evidence for this specific protein complex (PMID:20826760).
Supporting Evidence:
PMID:20826760
HMGB1 inhibits macrophage activity in efferocytosis through binding to the alphavbeta3-integrin.
|
|
GO:2000426
negative regulation of apoptotic cell clearance
|
IDA
PMID:20826760 HMGB1 inhibits macrophage activity in efferocytosis through ... |
ACCEPT |
Summary: HMGB1 inhibits phagocytosis of apoptotic cells.
Reason: HMGB1 binds phosphatidylserine on apoptotic cells and inhibits their clearance (PMID:20826760).
Supporting Evidence:
PMID:20826760
HMGB1 inhibits macrophage activity in efferocytosis through binding to the alphavbeta3-integrin.
|
|
GO:0034774
secretory granule lumen
|
TAS
Reactome:R-HSA-6798748 |
ACCEPT |
Summary: HMGB1 localizes to secretory granule lumen.
Reason: Valid TAS evidence. HMGB1 is secreted via secretory lysosomes.
|
|
GO:1904813
ficolin-1-rich granule lumen
|
TAS
Reactome:R-HSA-6800434 |
ACCEPT |
Summary: HMGB1 present in ficolin-1-rich granule lumen.
Reason: Valid Reactome TAS evidence for granule localization.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-166072 |
ACCEPT |
Summary: HMGB1 localizes to extracellular region in TLR signaling context.
Reason: Core localization. Reactome pathway annotation for HMGB1 in TLR signaling.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-166082 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization for alarmin function. Reactome TAS evidence.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-166091 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-166119 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-166284 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-166286 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-166362 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-166363 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-2201316 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-2201322 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-2262775 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-2262777 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-2559414 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-5432825 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-5602353 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-5602383 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-5602606 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-6804099 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-6804100 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-6805981 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-937022 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-937059 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-937079 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0032755
positive regulation of interleukin-6 production
|
IDA
PMID:26961863 AGEs and HMGB1 Increase Inflammatory Cytokine Production fro... |
ACCEPT |
Summary: HMGB1 induces IL-6 production.
Reason: Core alarmin function. Well-documented cytokine induction (PMID:26961863).
Supporting Evidence:
PMID:26961863
Mar 9. AGEs and HMGB1 Increase Inflammatory Cytokine Production from Human Placental Cells, Resulting in an Enhancement of Monocyte Migration.
|
|
GO:0032757
positive regulation of interleukin-8 production
|
IDA
PMID:26961863 AGEs and HMGB1 Increase Inflammatory Cytokine Production fro... |
ACCEPT |
Summary: HMGB1 induces IL-8/CXCL8 production.
Reason: Core alarmin function. Part of cytokine-inducing activity (PMID:26961863).
Supporting Evidence:
PMID:26961863
Mar 9. AGEs and HMGB1 Increase Inflammatory Cytokine Production from Human Placental Cells, Resulting in an Enhancement of Monocyte Migration.
|
|
GO:2000343
positive regulation of chemokine (C-X-C motif) ligand 2 production
|
IDA
PMID:26961863 AGEs and HMGB1 Increase Inflammatory Cytokine Production fro... |
ACCEPT |
Summary: HMGB1 induces CXCL2 production.
Reason: Core alarmin function. Part of chemokine-inducing activity.
Supporting Evidence:
PMID:26961863
Mar 9. AGEs and HMGB1 Increase Inflammatory Cytokine Production from Human Placental Cells, Resulting in an Enhancement of Monocyte Migration.
|
|
GO:0001786
phosphatidylserine binding
|
IDA
PMID:18768881 High mobility group protein-1 inhibits phagocytosis of apopt... |
ACCEPT |
Summary: HMGB1 binds phosphatidylserine on apoptotic cells.
Reason: Valid IDA evidence. HMGB1 binds PS and inhibits apoptotic cell clearance (PMID:18768881).
Supporting Evidence:
PMID:18768881
High mobility group protein-1 inhibits phagocytosis of apoptotic neutrophils through binding to phosphatidylserine.
|
|
GO:0002840
regulation of T cell mediated immune response to tumor cell
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: HMGB1 regulates T cell responses to tumors.
Reason: Pleiotropic immune effect. Supported by ISS.
|
|
GO:0032689
negative regulation of type II interferon production
|
IDA
PMID:22473704 HMGB1 conveys immunosuppressive characteristics on regulator... |
KEEP AS NON CORE |
Summary: HMGB1 can suppress IFN-gamma production.
Reason: Context-dependent immunomodulatory effect (PMID:22473704).
Supporting Evidence:
PMID:22473704
HMGB1 conveys immunosuppressive characteristics on regulatory and conventional T cells.
|
|
GO:0032733
positive regulation of interleukin-10 production
|
IDA
PMID:22473704 HMGB1 conveys immunosuppressive characteristics on regulator... |
KEEP AS NON CORE |
Summary: HMGB1 induces IL-10 production.
Reason: Immunomodulatory effect. IL-10 induction is context-dependent (PMID:22473704).
Supporting Evidence:
PMID:22473704
HMGB1 conveys immunosuppressive characteristics on regulatory and conventional T cells.
|
|
GO:0032735
positive regulation of interleukin-12 production
|
IMP
PMID:15944249 Release of high mobility group box 1 by dendritic cells cont... |
ACCEPT |
Summary: HMGB1 induces IL-12 production from dendritic cells.
Reason: Part of HMGB1's DC activation and Th1 polarization function (PMID:15944249).
Supporting Evidence:
PMID:15944249
Release of high mobility group box 1 by dendritic cells controls T cell activation via the receptor for advanced glycation end products.
|
|
GO:0034165
positive regulation of toll-like receptor 9 signaling pathway
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: HMGB1 enhances TLR9 signaling.
Reason: Core alarmin function. HMGB1 facilitates TLR9 activation by CpG-DNA.
|
|
GO:0035711
T-helper 1 cell activation
|
IDA
PMID:22473704 HMGB1 conveys immunosuppressive characteristics on regulator... |
KEEP AS NON CORE |
Summary: HMGB1 activates Th1 cells.
Reason: Downstream effect of HMGB1's immune signaling. Context-dependent.
Supporting Evidence:
PMID:22473704
HMGB1 conveys immunosuppressive characteristics on regulatory and conventional T cells.
|
|
GO:0042104
positive regulation of activated T cell proliferation
|
IMP
PMID:15944249 Release of high mobility group box 1 by dendritic cells cont... |
KEEP AS NON CORE |
Summary: HMGB1 promotes T cell proliferation.
Reason: Downstream pleiotropic effect of HMGB1's DC activation (PMID:15944249).
Supporting Evidence:
PMID:15944249
Release of high mobility group box 1 by dendritic cells controls T cell activation via the receptor for advanced glycation end products.
|
|
GO:0043277
apoptotic cell clearance
|
IDA
PMID:18768881 High mobility group protein-1 inhibits phagocytosis of apopt... |
ACCEPT |
Summary: HMGB1 regulates apoptotic cell clearance by inhibiting phagocytosis.
Reason: Valid IDA evidence. HMGB1 binds PS on apoptotic cells and inhibits clearance (PMID:18768881).
Supporting Evidence:
PMID:18768881
High mobility group protein-1 inhibits phagocytosis of apoptotic neutrophils through binding to phosphatidylserine.
|
|
GO:0043371
negative regulation of CD4-positive, alpha-beta T cell differentiation
|
IDA
PMID:22473704 HMGB1 conveys immunosuppressive characteristics on regulator... |
KEEP AS NON CORE |
Summary: HMGB1 negatively regulates CD4 T cell differentiation.
Reason: Context-dependent immunomodulatory effect (PMID:22473704).
Supporting Evidence:
PMID:22473704
HMGB1 conveys immunosuppressive characteristics on regulatory and conventional T cells.
|
|
GO:0045063
T-helper 1 cell differentiation
|
IMP
PMID:15944249 Release of high mobility group box 1 by dendritic cells cont... |
KEEP AS NON CORE |
Summary: HMGB1 promotes Th1 differentiation.
Reason: Downstream effect of DC activation (PMID:15944249).
Supporting Evidence:
PMID:15944249
Release of high mobility group box 1 by dendritic cells controls T cell activation via the receptor for advanced glycation end products.
|
|
GO:0097350
neutrophil clearance
|
IDA
PMID:18768881 High mobility group protein-1 inhibits phagocytosis of apopt... |
ACCEPT |
Summary: HMGB1 regulates neutrophil clearance.
Reason: Valid IDA evidence related to apoptotic cell clearance (PMID:18768881).
Supporting Evidence:
PMID:18768881
High mobility group protein-1 inhibits phagocytosis of apoptotic neutrophils through binding to phosphatidylserine.
|
|
GO:2001200
positive regulation of dendritic cell differentiation
|
IMP
PMID:15944249 Release of high mobility group box 1 by dendritic cells cont... |
KEEP AS NON CORE |
Summary: HMGB1 promotes dendritic cell differentiation.
Reason: Downstream pleiotropic effect of alarmin signaling (PMID:15944249).
Supporting Evidence:
PMID:15944249
Release of high mobility group box 1 by dendritic cells controls T cell activation via the receptor for advanced glycation end products.
|
|
GO:0002643
regulation of tolerance induction
|
IDA
PMID:18631454 Induction of immunological tolerance by apoptotic cells requ... |
ACCEPT |
Summary: Oxidized HMGB1 from apoptotic cells promotes immune tolerance.
Reason: Valid IDA evidence. Sulfonyl HMGB1 promotes tolerance through Cys-106 oxidation (PMID:18631454).
Supporting Evidence:
PMID:18631454
Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein.
|
|
GO:0007204
positive regulation of cytosolic calcium ion concentration
|
IDA
PMID:22370717 HMGB1 promotes recruitment of inflammatory cells to damaged ... |
ACCEPT |
Summary: HMGB1-CXCL12 complex induces calcium signaling via CXCR4.
Reason: Valid IDA evidence. CXCR4 signaling involves calcium mobilization (PMID:22370717).
Supporting Evidence:
PMID:22370717
HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4.
|
|
GO:0019958
C-X-C chemokine binding
|
IDA
PMID:22370717 HMGB1 promotes recruitment of inflammatory cells to damaged ... |
ACCEPT |
Summary: HMGB1 binds CXCL12 to form a heterocomplex.
Reason: Core function. HMGB1-CXCL12 binding is essential for CXCR4-mediated chemotaxis (PMID:22370717).
Supporting Evidence:
PMID:22370717
HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4.
|
|
GO:0070374
positive regulation of ERK1 and ERK2 cascade
|
IDA
PMID:22370717 HMGB1 promotes recruitment of inflammatory cells to damaged ... |
ACCEPT |
Summary: HMGB1-CXCL12 activates ERK1/2 via CXCR4.
Reason: Valid IDA evidence. ERK activation is part of CXCR4 signaling (PMID:22370717).
Supporting Evidence:
PMID:22370717
HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4.
|
|
GO:0090026
positive regulation of monocyte chemotaxis
|
IDA
PMID:22370717 HMGB1 promotes recruitment of inflammatory cells to damaged ... |
ACCEPT |
Summary: HMGB1-CXCL12 promotes monocyte chemotaxis.
Reason: Core extracellular function. Well-documented in PMID:22370717.
Supporting Evidence:
PMID:22370717
HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4.
|
|
GO:0003684
damaged DNA binding
|
IDA
PMID:17803946 HMGB1 is a cofactor in mammalian base excision repair. |
ACCEPT |
Summary: HMGB1 binds damaged DNA in base excision repair.
Reason: Core nuclear function. HMGB1 binds damaged DNA as part of BER (PMID:17803946).
Supporting Evidence:
PMID:17803946
HMGB1 is a cofactor in mammalian base excision repair.
|
|
GO:0016829
lyase activity
|
IDA
PMID:17803946 HMGB1 is a cofactor in mammalian base excision repair. |
UNDECIDED |
Summary: HMGB1 has lyase activity in BER context.
Reason: This annotation requires careful review. HMGB1 stimulates AP lyase activity but may not itself be the lyase.
Supporting Evidence:
PMID:17803946
HMGB1 is a cofactor in mammalian base excision repair.
|
|
GO:0032425
positive regulation of mismatch repair
|
IDA
PMID:15014079 Evidence for involvement of HMGB1 protein in human DNA misma... |
ACCEPT |
Summary: HMGB1 positively regulates mismatch repair.
Reason: Core nuclear function. HMGB1 is involved in MMR through MSH2 interaction (PMID:15014079).
Supporting Evidence:
PMID:15014079
2004 Mar 9. Evidence for involvement of HMGB1 protein in human DNA mismatch repair.
|
|
GO:0070182
DNA polymerase binding
|
IDA
PMID:17803946 HMGB1 is a cofactor in mammalian base excision repair. |
ACCEPT |
Summary: HMGB1 binds DNA polymerase beta in BER.
Reason: Valid IDA evidence. HMGB1 interacts with POLB in BER (PMID:17803946).
Supporting Evidence:
PMID:17803946
HMGB1 is a cofactor in mammalian base excision repair.
|
|
GO:0002218
activation of innate immune response
|
IDA
PMID:24971542 HMGB1-DNA complex-induced autophagy limits AIM2 inflammasome... |
ACCEPT |
Summary: HMGB1 activates innate immune response via AIM2 inflammasome.
Reason: Core alarmin function. HMGB1 promotes AIM2 inflammasome activation (PMID:24971542).
Supporting Evidence:
PMID:24971542
HMGB1-DNA complex-induced autophagy limits AIM2 inflammasome activation through RAGE.
|
|
GO:0032732
positive regulation of interleukin-1 production
|
IDA
PMID:12765338 Structural basis for the proinflammatory cytokine activity o... |
ACCEPT |
Summary: HMGB1 induces IL-1 production.
Reason: Core alarmin function. Well-documented cytokine induction (PMID:12765338).
Supporting Evidence:
PMID:12765338
Structural basis for the proinflammatory cytokine activity of high mobility group box 1.
|
|
GO:0032755
positive regulation of interleukin-6 production
|
IDA
PMID:12765338 Structural basis for the proinflammatory cytokine activity o... |
ACCEPT |
Summary: HMGB1 induces IL-6 production.
Reason: Core alarmin function. Well-documented (PMID:12765338).
Supporting Evidence:
PMID:12765338
Structural basis for the proinflammatory cytokine activity of high mobility group box 1.
|
|
GO:0032760
positive regulation of tumor necrosis factor production
|
IDA
PMID:12765338 Structural basis for the proinflammatory cytokine activity o... |
ACCEPT |
Summary: HMGB1 induces TNF production.
Reason: Core alarmin function. Well-documented (PMID:12765338).
Supporting Evidence:
PMID:12765338
Structural basis for the proinflammatory cytokine activity of high mobility group box 1.
|
|
GO:0043410
positive regulation of MAPK cascade
|
IDA
PMID:12765338 Structural basis for the proinflammatory cytokine activity o... |
ACCEPT |
Summary: HMGB1 activates MAPK signaling.
Reason: Valid IDA evidence. MAPK activation through receptor signaling (PMID:12765338).
Supporting Evidence:
PMID:12765338
Structural basis for the proinflammatory cytokine activity of high mobility group box 1.
|
|
GO:0046330
positive regulation of JNK cascade
|
IDA
PMID:12765338 Structural basis for the proinflammatory cytokine activity o... |
ACCEPT |
Summary: HMGB1 activates JNK signaling.
Reason: Valid IDA evidence. JNK activation through receptor signaling (PMID:12765338).
Supporting Evidence:
PMID:12765338
Structural basis for the proinflammatory cytokine activity of high mobility group box 1.
|
|
GO:0001530
lipopolysaccharide binding
|
IDA
PMID:21660935 Identification of lipopolysaccharide-binding peptide regions... |
ACCEPT |
Summary: HMGB1 binds LPS and transfers it to CD14.
Reason: Core function. HMGB1 binds LPS and enhances TLR4 signaling (PMID:21660935).
Supporting Evidence:
PMID:21660935
Aug 4. Identification of lipopolysaccharide-binding peptide regions within HMGB1 and their effects on subclinical endotoxemia in a mouse model.
|
|
GO:0000400
four-way junction DNA binding
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: HMGB1 binds four-way junction DNA structures.
Reason: Core function. HMGB1 preferentially binds non-canonical DNA structures including cruciform DNA.
|
|
GO:0000405
bubble DNA binding
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: HMGB1 binds bubble DNA structures.
Reason: Core function. HMGB1 binds distorted DNA structures.
|
|
GO:0008301
DNA binding, bending
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: HMGB1 binds and bends DNA.
Reason: Core molecular function. DNA bending is fundamental to HMGB1's chromatin function.
|
|
GO:0032392
DNA geometric change
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: HMGB1 induces DNA geometric changes.
Reason: Core function. HMGB1 bends DNA and alters its geometry.
|
|
GO:0097100
supercoiled DNA binding
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: HMGB1 binds supercoiled DNA.
Reason: Core function. HMGB1 preferentially binds non-canonical DNA including supercoiled DNA.
|
|
GO:0003723
RNA binding
|
HDA
PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... |
ACCEPT |
Summary: HMGB1 binds RNA as a nucleic acid biosensor.
Reason: HMGB1 binds various nucleic acids including RNA. HDA evidence from interactome capture.
Supporting Evidence:
PMID:22658674
May 31. Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
|
|
GO:0003723
RNA binding
|
HDA
PMID:22681889 The mRNA-bound proteome and its global occupancy profile on ... |
ACCEPT |
Summary: HMGB1 binds RNA.
Reason: Valid HDA evidence from interactome studies (PMID:22681889).
Supporting Evidence:
PMID:22681889
The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-6798748 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-6800434 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-879411 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-NUL-997411 |
ACCEPT |
Summary: HMGB1 in extracellular region.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-266204 |
ACCEPT |
Summary: HMGB1 in nucleoplasm.
Reason: Core localization. Reactome TAS evidence for V(D)J recombination.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-6805981 |
ACCEPT |
Summary: HMGB1 in nucleoplasm.
Reason: Core localization. Reactome TAS evidence.
|
|
GO:0006954
inflammatory response
|
IDA
PMID:23146691 Emodin-6-O-β-D-glucoside inhibits HMGB1-induced inflammatory... |
ACCEPT |
Summary: HMGB1 promotes inflammatory response.
Reason: Core alarmin function. Well-documented (PMID:23146691).
Supporting Evidence:
PMID:23146691
2012 Nov 9. Emodin-6-O-β-D-glucoside inhibits HMGB1-induced inflammatory responses in vitro and in vivo.
|
|
GO:0043537
negative regulation of blood vessel endothelial cell migration
|
IDA
PMID:23148224 High mobility group Box 1 inhibits human pulmonary artery en... |
KEEP AS NON CORE |
Summary: HMGB1 can inhibit endothelial migration via TLR4.
Reason: Context-dependent pleiotropic effect (PMID:23148224).
Supporting Evidence:
PMID:23148224
2012 Nov 12. High mobility group Box 1 inhibits human pulmonary artery endothelial cell migration via a Toll-like receptor 4- and interferon response factor 3-dependent mechanism(s).
|
|
GO:0005615
extracellular space
|
IDA
PMID:19841752 Linking innate and adaptive immunity: human Vgamma9Vdelta2 T... |
ACCEPT |
Summary: HMGB1 in extracellular space.
Reason: Core localization. IDA evidence.
Supporting Evidence:
PMID:19841752
Linking innate and adaptive immunity: human Vgamma9Vdelta2 T cells enhance CD40 expression and HMGB-1 secretion.
|
|
GO:0009986
cell surface
|
IDA
PMID:19841752 Linking innate and adaptive immunity: human Vgamma9Vdelta2 T... |
ACCEPT |
Summary: HMGB1 on cell surface.
Reason: Valid IDA evidence. HMGB1 on surface of activated cells (PMID:19841752).
Supporting Evidence:
PMID:19841752
Linking innate and adaptive immunity: human Vgamma9Vdelta2 T cells enhance CD40 expression and HMGB-1 secretion.
|
|
GO:0005515
protein binding
|
IPI
PMID:19505873 Complementary quantitative proteomics reveals that transcrip... |
ACCEPT |
Summary: HMGB1 binds proteins.
Reason: Valid IPI evidence from interactome study.
Supporting Evidence:
PMID:19505873
Epub 2009 Jun 7. Complementary quantitative proteomics reveals that transcription factor AP-4 mediates E-box-dependent complex formation for transcriptional repression of HDM2.
|
|
GO:0031175
neuron projection development
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: HMGB1 involved in neuron projection development via RAGE.
Reason: Tissue-specific pleiotropic effect through RAGE signaling.
|
|
GO:0043388
positive regulation of DNA binding
|
IDA
PMID:11748232 HMGB1 and HMGB2 cell-specifically down-regulate the p53- and... |
ACCEPT |
Summary: HMGB1 enhances DNA binding of transcription factors.
Reason: Core function. HMGB1 enhances DNA binding of p53 and other transcription factors (PMID:11748232).
Supporting Evidence:
PMID:11748232
Dec 17. HMGB1 and HMGB2 cell-specifically down-regulate the p53- and p73-dependent sequence-specific transactivation from the human Bax gene promoter.
|
|
GO:0050786
RAGE receptor binding
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: HMGB1 binds RAGE receptor.
Reason: Core alarmin function. RAGE binding is essential for many HMGB1 extracellular effects.
|
|
GO:0001773
myeloid dendritic cell activation
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: HMGB1 activates dendritic cells.
Reason: Downstream effect of alarmin signaling. ISS evidence.
|
|
GO:0002407
dendritic cell chemotaxis
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: HMGB1 promotes dendritic cell chemotaxis.
Reason: Downstream pleiotropic effect. ISS evidence.
|
|
GO:0002437
inflammatory response to antigenic stimulus
|
IEP
PMID:19841752 Linking innate and adaptive immunity: human Vgamma9Vdelta2 T... |
ACCEPT |
Summary: HMGB1 elevated during inflammatory response to antigen.
Reason: Valid IEP evidence. HMGB1 elevated in inflammatory contexts.
Supporting Evidence:
PMID:19841752
Linking innate and adaptive immunity: human Vgamma9Vdelta2 T cells enhance CD40 expression and HMGB-1 secretion.
|
|
GO:0003684
damaged DNA binding
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: HMGB1 binds damaged DNA.
Reason: Core function. ISS evidence supporting damaged DNA binding.
|
|
GO:0005125
cytokine activity
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: HMGB1 has cytokine activity.
Reason: Core extracellular function. Disulfide HMGB1 has cytokine-like activity. ISS evidence.
|
|
GO:0033151
V(D)J recombination
|
IDA
PMID:9166431 V(D)J recombination: modulation of RAG1 and RAG2 cleavage ac... |
ACCEPT |
Summary: HMGB1 is a cofactor in V(D)J recombination.
Reason: Core nuclear function. HMGB1 stimulates RAG cleavage in V(D)J recombination (PMID:9166431).
Supporting Evidence:
PMID:9166431
V(D)J recombination: modulation of RAG1 and RAG2 cleavage activity on 12/23 substrates by whole cell extract and DNA-bending proteins.
|
|
GO:0042056
chemoattractant activity
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: HMGB1 has chemoattractant activity.
Reason: Core extracellular function. All-thiol HMGB1 with CXCL12 is chemotactic. ISS evidence.
|
|
GO:0043065
positive regulation of apoptotic process
|
IDA
PMID:19800306 Effect of high mobility group box-1 protein on apoptosis of ... |
KEEP AS NON CORE |
Summary: HMGB1 can promote apoptosis in certain contexts.
Reason: Context-dependent effect (PMID:19800306). Not a core function.
Supporting Evidence:
PMID:19800306
Epub 2009 Oct 1. Effect of high mobility group box-1 protein on apoptosis of peritoneal macrophages.
|
|
GO:0003690
double-stranded DNA binding
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: HMGB1 binds double-stranded DNA through its HMG-box domains A and B. This is a well-established core function.
Reason: DNA binding is a fundamental function of HMGB1. The protein binds dsDNA through its HMG-box domains (PMID:8339930). ISS transfer from ortholog is appropriate.
Supporting Evidence:
PMID:8339930
The mammalian high mobility group proteins HMG1 and HMG2 are abundant, chromatin-associated proteins
|
|
GO:0003697
single-stranded DNA binding
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: HMGB1 has been shown to bind single-stranded DNA in addition to dsDNA through its HMG-box domains.
Reason: HMGB1 binds various DNA structures including ssDNA. ISS transfer from ortholog data is appropriate given the conserved DNA-binding HMG-box domains.
|
|
GO:0005515
protein binding
|
IPI
PMID:11748232 HMGB1 and HMGB2 cell-specifically down-regulate the p53- and... |
MODIFY |
Summary: This study demonstrates HMGB1 physically interacts with p53 and p73 transcription factors, enhancing their DNA binding. The generic protein binding term should be replaced with a more specific term.
Reason: HMGB1 interacts with p53 and p73 transcription factors to modulate their DNA binding activity (PMID:11748232). The generic protein binding term is uninformative; a more specific term for transcription factor binding is appropriate.
Proposed replacements:
DNA-binding transcription factor binding
Supporting Evidence:
PMID:11748232
HMGB1 physically interacts with two splicing variants of p73, alpha and beta (pull-down assay), and enhances binding of p73 to specific cognate DNA sites
|
|
GO:0005634
nucleus
|
IDA
PMID:19223331 HMGB1 and HMGB2 proteins up-regulate cellular expression of ... |
ACCEPT |
Summary: HMGB1 is a chromatin-associated nuclear protein that shuttles between nucleus and cytoplasm. Nuclear localization is well-established.
Reason: Nuclear localization is a core characteristic of HMGB1 as a chromatin-associated protein (PMID:19223331). The protein is predominantly nuclear in basal state.
Supporting Evidence:
PMID:19223331
HMGB1 is associated with chromosomes in mitosis and due to its extreme mobility in the cell the protein is continuously exchanged between nucleus and cytoplasm
|
|
GO:0006265
DNA topological change
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: HMGB1 binding causes DNA bending and topological changes. The protein can promote DNA circularization and alter DNA topology.
Reason: HMGB1 induces DNA topological changes through its DNA-bending activity (PMID:8339930). This is a core biochemical function demonstrated by circularization assays.
Supporting Evidence:
PMID:8339930
HMG1 and HMG2 can bend DNA extremely efficiently, forming circles as small as 66 bp
|
|
GO:0006310
DNA recombination
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: HMGB1 participates in DNA recombination including V(D)J recombination by facilitating DNA bending and promoting assembly of nucleoprotein complexes.
Reason: HMGB1 promotes DNA recombination by facilitating DNA flexibility and nucleoprotein complex assembly (PMID:8339930). This is a core nuclear function.
Supporting Evidence:
PMID:8339930
these proteins can substitute for the prokaryotic DNA-bending protein HU in promoting the assembly of the Hin invertasome, an intermediate structure in Hin-mediated site-specific DNA inversion
|
|
GO:0008301
DNA binding, bending
|
IMP
PMID:19223331 HMGB1 and HMGB2 proteins up-regulate cellular expression of ... |
ACCEPT |
Summary: HMGB1 DNA bending is a core function. The study showed that HMGB1, but not a mutant incapable of DNA bending, activates the topo IIalpha promoter.
Reason: DNA bending is a fundamental function of HMGB1 demonstrated by IMP evidence. The study shows DNA bending is required for HMGB1 to activate topo IIalpha promoter (PMID:19223331).
Supporting Evidence:
PMID:19223331
HMGB1, but not a mutant of HMGB1 incapable of DNA bending, up-regulates the activity of the topo IIalpha promoter in human cells
|
|
GO:0043388
positive regulation of DNA binding
|
IDA
PMID:19223331 HMGB1 and HMGB2 proteins up-regulate cellular expression of ... |
ACCEPT |
Summary: HMGB1 enhances DNA binding of transcription factors like NF-Y and p53/p73 family members by modulating DNA structure.
Reason: HMGB1 positively regulates DNA binding by modulating transcription factor NF-Y binding to promoters (PMID:19223331). This is a core function related to its transcriptional coregulator role.
Supporting Evidence:
PMID:19223331
Our experiments suggest a mechanism of up-regulation of cellular expression of topo IIalpha by HMGB1/2 in pRb-negative cells by modulation of binding of transcription factor NF-Y to the topo IIalpha promoter
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
IDA
PMID:19223331 HMGB1 and HMGB2 proteins up-regulate cellular expression of ... |
ACCEPT |
Summary: HMGB1 upregulates topo IIalpha promoter activity through luciferase reporter assays in pRb-negative cells.
Reason: HMGB1 positively regulates transcription by RNA pol II as demonstrated by luciferase reporter assays showing upregulation of topo IIalpha promoter (PMID:19223331). This is a core transcriptional coregulator function.
Supporting Evidence:
PMID:19223331
Using luciferase gene reporter assay we have demonstrated that HMGB1, but not a mutant of HMGB1 incapable of DNA bending, up-regulated the activity of human topo IIalpha promoter in human cells that lack functional retinoblastoma protein pRb
|
|
GO:0140297
DNA-binding transcription factor binding
|
IPI
PMID:19223331 HMGB1 and HMGB2 proteins up-regulate cellular expression of ... |
ACCEPT |
Summary: HMGB1 interacts with transcription factors including NF-Y to modulate their DNA binding activity and transcriptional output.
Reason: HMGB1 interacts with and modulates the activity of DNA-binding transcription factors like NF-Y (PMID:19223331) and p53/p73 family members. This is a specific and accurate molecular function term.
Supporting Evidence:
PMID:19223331
HMGB1 also interacts weakly with a number of proteins, including transcriptional factors, site-specific recombination and DNA repair proteins
|
|
GO:0005634
nucleus
|
IDA
PMID:8339930 The nonspecific DNA-binding and -bending proteins HMG1 and H... |
ACCEPT |
Summary: HMGB1 is an abundant chromatin-associated nuclear protein. Nuclear localization is fundamental to its function.
Reason: Nuclear localization is a core characteristic of HMGB1 as an abundant chromatin-associated protein (PMID:8339930). This is well-established and fundamental to its biological role.
Supporting Evidence:
PMID:8339930
The mammalian high mobility group proteins HMG1 and HMG2 are abundant, chromatin-associated proteins
|
|
GO:0000793
condensed chromosome
|
IDA
PMID:12925773 Association of chromatin proteins high mobility group box (H... |
ACCEPT |
Summary: HMGB1 associates with condensed chromosomes during mitosis. Live cell imaging shows the protein exchanges rapidly between free and chromosome-bound forms.
Reason: HMGB1 associates with condensed chromatin during mitosis as shown by fluorescent protein tagging in live cells (PMID:12925773). This is a core function related to its chromatin-binding role.
Supporting Evidence:
PMID:12925773
HMGB1 and 2 were shown to be present under two forms in mitotic cells, i.e., free and associated with the condensed chromatin, which rapidly exchange
|
|
GO:0005515
protein binding
|
IPI
PMID:8006019 The high mobility group protein HMG1 can reversibly inhibit ... |
MODIFY |
Summary: This study demonstrates HMGB1 physically interacts with TBP (TATA-binding protein) to inhibit preinitiation complex assembly. The generic term should be replaced with a more specific binding term.
Reason: HMGB1 interacts with TBP to form an HMG1.TBP.promoter complex that blocks TFIIB binding (PMID:8006019). The generic protein binding term is uninformative; a more specific term for transcription machinery component binding is appropriate.
Proposed replacements:
DNA-binding transcription factor binding
Supporting Evidence:
PMID:8006019
purified mammalian HMG1, as well as recombinant human HMG1, can interact with TATA-binding protein (TBP) in the presence of a TATA box-containing oligonucleotide to form a specific HMG1.TBP.promoter complex
|
|
GO:0017055
negative regulation of RNA polymerase II transcription preinitiation complex assembly
|
IDA
PMID:8006019 The high mobility group protein HMG1 can reversibly inhibit ... |
ACCEPT |
Summary: HMGB1 interacts with TBP to form a complex that prevents TFIIB binding and blocks preinitiation complex formation. In vitro, HMGB1 inhibits transcription by RNA pol II over 30-fold.
Reason: HMGB1 inhibits preinitiation complex assembly by binding TBP and blocking TFIIB recruitment (PMID:8006019). This is a well-characterized transcriptional regulatory function with direct assay evidence.
Supporting Evidence:
PMID:8006019
This complex prevents TFIIB binding to TBP and consequently blocks formation of the preinitiation complex
|
provider: falcon
model: Edison Scientific Literature
cached: false
start_time: '2026-01-19T08:57:54.510549'
end_time: '2026-01-19T09:07:05.802690'
duration_seconds: 551.29
template_file: templates/gene_research_go_focused.md
template_variables:
organism: human
gene_id: HMGB1
gene_symbol: HMGB1
uniprot_accession: P09429
protein_description: 'RecName: Full=High mobility group protein B1; AltName: Full=High
mobility group protein 1; Short=HMG-1;'
gene_info: Name=HMGB1 {ECO:0000312|HGNC:HGNC:4983}; Synonyms=HMG1;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the HMGB family. .
protein_domains: HMG_box_dom. (IPR009071); HMG_box_dom_sf. (IPR036910); HMG_boxA_CS.
(IPR017967); HMGB. (IPR050342); HMG_box (PF00505)
provider_config:
timeout: 600
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parameters:
allowed_domains: []
temperature: 0.1
citation_count: 48
BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.
DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'HMGB1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information
Please provide a comprehensive research report on the gene HMGB1 (gene ID: HMGB1, UniProt: P09429) in human.
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.
BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.
DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'HMGB1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information
Please provide a comprehensive research report on the gene HMGB1 (gene ID: HMGB1, UniProt: P09429) in human.
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Research plan status: Verified target identity and created a concise artifact for reference. Below is the comprehensive report with recent developments, applications, expert perspectives, and quantitative statistics. An at-a-glance summary table is embedded for quick lookup.
| Topic | Key facts | Receptors/Partners | Quantitative data (if any) | Sources |
|---|---|---|---|---|
| Identity & domains | 215 aa non-histone chromatin protein; A-box (≈aa9–79), B-box (≈aa95–163), acidic C-tail; NLS1 aa28–44, NLS2 aa179–185; HMGB family | DNA, nucleosomes, histone H1 | ~25–30 kDa | (yuan2024hmgb1asan pages 1-3, lv2024multiplefunctionsof pages 1-2, datta2024highmobilitygroup pages 1-2, starkova2023structureandfunctions pages 1-2) |
| Redox isoforms & activities | All-thiol (fully reduced): chemotactic; Disulfide (C23–C45 SS; C106 thiol): cytokine-inducing; Fully oxidized: inactive | All-thiol forms CXCL12 heterocomplex → CXCR4; Disulfide binds TLR4/MD-2; RAGE binds HMGB1 complexes | — | (yuan2024hmgb1asan pages 1-3, pirani2024tumorcellsexpress pages 1-2, datta2024highmobilitygroup pages 1-2) |
| PTMs controlling localization & secretion | Acetylation, phosphorylation, methylation, ADP‑ribosylation modulate nuclear export; acetylation of NLS lysines promotes cytoplasmic translocation; active non-classical (lysosomal/exocytosis) vs passive release from necrosis | — | — | (passali2025hmgb1asa pages 2-4, yuan2024hmgb1asan pages 1-3, datta2024highmobilitygroup pages 11-13) |
| Core signaling pathways & regulated cell-death links | Activates NF-κB, MAPK/ERK, PI3K/AKT, STAT3; primes NLRP3 inflammasome; linked to pyroptosis and ferroptosis; cytoplasmic HMGB1 promotes autophagy (Beclin‑1) | TLR4 (MyD88/TRIF), RAGE, TLR2, TLR9 (with DNA), CXCR4 (via CXCL12) | — | (fan2024hmgb1rageaxisin pages 1-2, datta2024highmobilitygroup pages 1-2, passali2025hmgb1asa pages 2-4, bosakhar2025investigatingtheinflammatory pages 57-61) |
| Subcellular / extracellular localization | Predominantly nuclear (chromatin/DNA chaperone); translocates to cytosol, mitochondria, lysosomes; released extracellularly as DAMP/alarmin | Intracellular partners: DNA, histones, Beclin‑1; Extracellular: TLRs, RAGE, CXCL12 | — | (datta2024highmobilitygroup pages 1-2, starkova2023structureandfunctions pages 1-2, yuan2024hmgb1asan pages 1-3) |
| 2023–2024 key advances | Complement C1s cleaves HMGB1 producing an anti-inflammatory fragment (F3); HMGB1 can deform nucleosomal DNA enabling co-occupancy/competition with linker histone H1; MS protocol distinguishes red vs oxidized HMGB1 in cells; tumor cells maintain red‑HMGB1 to boost CXCR4-mediated migration | C1s-derived fragments modulate TLR4/MD-2 binding; CXCL12/HMGB1 → CXCR4 | MS-based isoform discrimination demonstrated; functional F3 fragment identified (anti-inflammatory) | (lorvellec2023hmgb1cleavageby pages 13-14, palone2016fecalhmgb1reveals pages 1-2, pirani2024tumorcellsexpress pages 1-2) |
| Biomarker applications & statistics | Serum HMGB1 elevated in sepsis and correlates with severity/prognosis; fecal HMGB1 detects microscopic IBD activity even in endoscopic remission; early HMGB1 predicts AKI/MOF in trauma model | — | Sepsis prognosis: AUC 0.781; cutoff 395.80 ng/mL (survival) (n=86 sepsis; survivors 60, deaths 26) (jiang2024correlationofserum pages 2-4, jiang2024correlationofserum pages 4-7). Trauma (swine) 12‑h HMGB1: AUROC AKI 0.81 / MOF 0.89; cutoff 36.41 ng/mL (n=39) (yang2024anearlyhmgb1 pages 1-2). IBD fecal cohorts: pediatric n=85, adult n=119; fecal HMGB1 vs fecal calprotectin r=0.60 (peds), r=0.72 (adult); fecal HMGB1 detects histologic inflammation in endoscopic remission (palone2016fecalhmgb1reveals pages 1-2, palone2014roleofhmgb1 pages 3-6, palone2016fecalhmgb1reveals pages 7-8). | (jiang2024correlationofserum pages 2-4, jiang2024correlationofserum pages 4-7, yang2024anearlyhmgb1 pages 1-2, palone2016fecalhmgb1reveals pages 1-2, palone2014roleofhmgb1 pages 3-6, palone2016fecalhmgb1reveals pages 7-8) |
| Therapeutic strategies & real-world implementations | Direct HMGB1 binders/inhibitors (glycyrrhizin); small-molecule inhibitors reducing release (e.g., nafamostat-like agents); A-box or C1s-derived fragments act as antagonists; strategies to inhibit RAGE or disrupt CXCL12/HMGB1 heterocomplex; mostly preclinical/early translational; limited clinical/observational studies | Glycyrrhizin blocks HMGB1–RAGE/TLR4 signaling; A-box/F3 fragments antagonize TLR4 binding | Clinical trial evidence limited; translational/preclinical efficacy reported across IRI, lung/liver injury, cancer models | (datta2024highmobilitygroup pages 11-13, fan2024hmgb1rageaxisin pages 1-2, lorvellec2023hmgb1cleavageby pages 13-14, datta2024highmobilitygroup pages 1-2) |
Table: Concise, citable summary of human HMGB1 (UniProt P09429) covering structure, redox/PTM regulation, receptors, key pathways, 2023–24 advances, biomarker statistics, and therapeutic strategies with source citations for quick reference.
Comprehensive research report on HMGB1 (Human; UniProt P09429)
Identity verification and core definitions
- Gene/protein identity: HMGB1 (HGNC:4983), UniProt P09429, Homo sapiens. A 215–amino-acid, non-histone chromatin protein of the HMGB family with two HMG-box DNA-binding domains (A-box ~aa9–79, B-box ~aa95–163) and an acidic C-terminal tail. Contains nuclear localization signals NLS1 (aa28–44) and NLS2 (aa179–185). Functions as an architectural chromatin factor in the nucleus and a prototypical alarmin/DAMP extracellularly (structure-function and domain mapping supported in 2024–2020 sources) (yuan2024hmgb1asan pages 1-3, lv2024multiplefunctionsof pages 1-2, datta2024highmobilitygroup pages 1-2, starkova2023structureandfunctions pages 1-2). URLs: https://doi.org/10.1007/s10565-024-09893-2; https://doi.org/10.3389/fonc.2024.1384109; https://doi.org/10.3390/cells13231946; https://doi.org/10.3390/ijms24098334.
Primary functions and localization
- Nuclear: Binds and bends DNA, modulates nucleosome structure, assists transcription, replication, and DNA damage repair; interacts with histones (including H1) and can facilitate nucleosome sliding and access (datta2024highmobilitygroup pages 1-2, starkova2023structureandfunctions pages 1-2). URL: https://doi.org/10.3390/cells13231946; https://doi.org/10.3390/ijms24098334.
- Cytoplasmic/organelle: Shuttles to cytoplasm (regulated by PTMs), localizes to mitochondria/lysosomes; interacts with Beclin-1 to promote autophagy; participates in inflammasome/pyroptosis pathways (datta2024highmobilitygroup pages 1-2, passali2025hmgb1asa pages 2-4). URL: https://doi.org/10.3390/cells13231946; https://doi.org/10.3390/jcm14155392.
- Extracellular: Released passively by necrotic cells or actively via non-classical secretion; acts as a DAMP/alarmin engaging TLR2/4, RAGE, or forms a chemotactic heterocomplex with CXCL12 to signal via CXCR4 (passali2025hmgb1asa pages 2-4, yuan2024hmgb1asan pages 1-3, fan2024hmgb1rageaxisin pages 1-2). URLs: https://doi.org/10.3390/jcm14155392; https://doi.org/10.1007/s10565-024-09893-2; https://doi.org/10.3389/fonc.2024.1336191.
Redox isoforms and receptor/pathway specificity
- All-thiol (fully reduced) HMGB1: Does not activate TLR4/MD-2 by itself; forms CXCL12/HMGB1 heterocomplex that potentiates CXCR4 signaling and chemotaxis/tissue repair. Human tumor cells maintain red-HMGB1 and release thioredoxin/thioredoxin reductase to sustain CXCR4-mediated migration (mass-spec confirmed discrimination of red vs oxidized isoforms in cell lysates) (yuan2024hmgb1asan pages 1-3, pirani2024tumorcellsexpress pages 1-2). URLs: https://doi.org/10.1007/s10565-024-09893-2; https://doi.org/10.3389/fimmu.2024.1358800.
- Disulfide HMGB1 (C23–C45 disulfide; C106 reduced): Binds TLR4/MD-2 and induces proinflammatory cytokines via MyD88–NF-κB and MAPKs (yuan2024hmgb1asan pages 1-3, passali2025hmgb1asa pages 2-4). URLs: https://doi.org/10.1007/s10565-024-09893-2; https://doi.org/10.3390/jcm14155392.
- Fully oxidized/sulfonyl HMGB1: Lacks chemokine/cytokine-inducing activity (yuan2024hmgb1asan pages 1-3, passali2025hmgb1asa pages 2-4). URLs: https://doi.org/10.1007/s10565-024-09893-2; https://doi.org/10.3390/jcm14155392.
- RAGE engagement: Extracellular HMGB1 (and HMGB1–ligand complexes) bind RAGE to activate NF-κB, MAPK/ERK, PI3K/AKT and STAT3 pathways, promoting proliferation, migration, angiogenesis; RAGE also mediates endocytosis of HMGB1 complexes (fan2024hmgb1rageaxisin pages 1-2, passali2025hmgb1asa pages 2-4). URLs: https://doi.org/10.3389/fonc.2024.1336191; https://doi.org/10.3390/jcm14155392.
Post-translational modifications (PTMs) and secretion
- PTMs: Acetylation of NLS lysines promotes nucleocytoplasmic translocation and active secretion; phosphorylation, methylation, and poly-ADP-ribosylation further modulate DNA binding and trafficking. Oxidation controls extracellular activity; redox maintained by thioredoxin systems (passali2025hmgb1asa pages 2-4, yuan2024hmgb1asan pages 1-3, pirani2024tumorcellsexpress pages 1-2, datta2024highmobilitygroup pages 11-13). URLs: https://doi.org/10.3390/jcm14155392; https://doi.org/10.1007/s10565-024-09893-2; https://doi.org/10.3389/fimmu.2024.1358800; https://doi.org/10.3390/cells13231946.
- Secretion: Non-classical/lysosomal exocytosis from activated immune/structural cells vs passive release during necrosis/pyroptosis (passali2025hmgb1asa pages 2-4). URL: https://doi.org/10.3390/jcm14155392.
Signaling and regulated cell death
- Pathways: TLR4–MyD88/TRIF→NF-κB and MAPKs (ERK, JNK, p38); RAGE→NF-κB, PI3K/AKT, ERK, STAT3; HMGB1–DNA complexes→TLR9 via RAGE-mediated endocytosis; CXCL12/HMGB1→CXCR4-mediated chemotaxis (fan2024hmgb1rageaxisin pages 1-2, passali2025hmgb1asa pages 2-4, bosakhar2025investigatingtheinflammatory pages 57-61). URLs: https://doi.org/10.3389/fonc.2024.1336191; https://doi.org/10.3390/jcm14155392; —.
- Cell death: HMGB1 primes inflammasomes (NLRP3) via TLR4; contributes to pyroptosis; is implicated in ferroptosis; cytoplasmic HMGB1 promotes autophagy through Beclin‑1 interaction (datta2024highmobilitygroup pages 1-2, passali2025hmgb1asa pages 2-4, bosakhar2025investigatingtheinflammatory pages 57-61). URLs: https://doi.org/10.3390/cells13231946; https://doi.org/10.3390/jcm14155392; —.
Recent developments (2023–2024)
- Complement C1s cleavage: C1s cleaves HMGB1 to generate fragments; a defined N-terminal fragment (F3) binds TLR4 without signaling, acting as a potent endogenous antagonist that can dampen inflammation. Mass spectrometry mapped cleavage sites; proposes stepwise A- then B-box engagement of TLR4/MD-2 and shows how fragments modulate this (lorvellec2023hmgb1cleavageby pages 13-14). URL: https://doi.org/10.3389/fimmu.2023.1151731.
- Chromatin architecture: Cryo-EM and biophysical work show HMGB1 deforms nucleosomal DNA and counteracts linker histone H1 suppression of DNA accessibility without displacing H1, supporting its role as a chromatin “enabler” that increases dynamics (preprint 2024) (palone2016fecalhmgb1reveals pages 1-2). URL: https://doi.org/10.1101/2024.08.23.609244.
- Redox isoform quantitation in cancer: A mass spectrometry protocol discriminated reduced vs oxidized HMGB1 in cancer cells; tumors maintain red-HMGB1 and an active thioredoxin system to potentiate CXCL12/HMGB1–CXCR4 migration, nominating disruption of this heterocomplex as a target (pirani2024tumorcellsexpress pages 1-2). URL: https://doi.org/10.3389/fimmu.2024.1358800.
Applications and real-world implementations
- Sepsis biomarker (serum): In a retrospective single-center cohort of 86 sepsis patients (60 survivors/26 deaths), serum HMGB1 correlated with severity (APACHE II r=0.709; P<0.001) and predicted prognosis: AUC 0.781 (95% CI 0.674–0.888), optimal cutoff 395.80 ng/mL (sensitivity 57.7%, specificity 91.7%); combining H-FABP, sTREM-1, HMGB1 improved AUC to 0.834 (95% CI 0.739–0.930) (jiang2024correlationofserum pages 2-4, jiang2024correlationofserum pages 4-7, jiang2024correlationofserum pages 1-2). URL: https://doi.org/10.62347/kelz4296.
- Trauma AKI/MOF prediction (translational swine): 39 swine model of smoke inhalation + burns: 12-hour HMGB1 predicted AKI and MOF before creatinine rise; AUROC 0.81 (AKI) and 0.89 (MOF), optimal cutoff 36.41 ng/mL at 12 h; AKI group HMGB1 73.07±18.66 ng/mL vs 31.64±4.15 ng/mL in non-AKI (p<0.01) (yang2024anearlyhmgb1 pages 1-2). URL: https://doi.org/10.3389/fimmu.2024.1447597.
- IBD fecal HMGB1: In pediatric (n=85) and adult (n=119) cohorts, fecal HMGB1 was elevated and correlated with fecal calprotectin (r=0.60 peds; r=0.72 adult; P<0.001). Crucially, in patients in clinical and endoscopic remission, fecal HMGB1 aligned with histological inflammation (Geboes≥3.1; CGHAS/IGHAS>4), indicating utility for detecting microscopic inflammation/mucosal healing (palone2016fecalhmgb1reveals pages 1-2, palone2016fecalhmgb1reveals pages 7-8). URLs: https://doi.org/10.1097/mib.0000000000000938.
Therapeutic targeting and implementations
- Direct HMGB1 inhibitors: Glycyrrhizin and related compounds bind HMGB1 and can suppress HMGB1–TLR4/RAGE-driven inflammation (mechanistic and preclinical evidence across organ injury contexts) (datta2024highmobilitygroup pages 11-13, fan2024hmgb1rageaxisin pages 1-2). URLs: https://doi.org/10.3390/cells13231946; https://doi.org/10.3389/fonc.2024.1336191.
- Antagonist domains/fragments: The HMGB1 A-box and the complement C1s-derived F3 fragment act as antagonists of TLR4/MD-2 engagement, reducing inflammatory signaling in preclinical models (lorvellec2023hmgb1cleavageby pages 13-14). URL: https://doi.org/10.3389/fimmu.2023.1151731.
- Axis disruption: In cancer, targeting the CXCL12/HMGB1 heterocomplex (to reduce CXCR4-mediated migration) and RAGE inhibition are rational strategies; tumors maintain red-HMGB1 to promote migration (pirani2024tumorcellsexpress pages 1-2, fan2024hmgb1rageaxisin pages 1-2). URLs: https://doi.org/10.3389/fimmu.2024.1358800; https://doi.org/10.3389/fonc.2024.1336191.
Expert perspectives and interpretations
- Consensus across recent reviews: HMGB1’s biological activity is governed by redox state, PTMs, and macromolecular complex formation, which together dictate receptor usage and context (repair vs inflammation). Therapeutic success likely requires isoform- and context-aware interventions (passali2025hmgb1asa pages 2-4, datta2024highmobilitygroup pages 1-2, fan2024hmgb1rageaxisin pages 1-2). URLs: https://doi.org/10.3390/jcm14155392; https://doi.org/10.3390/cells13231946; https://doi.org/10.3389/fonc.2024.1336191.
Limitations and open questions
- Standardization: Clinical HMGB1 assays vary (ELISA kits, sample handling), and few studies report isoform-specific measurements in patients. Redox/isoform-resolved quantitation (as shown in 2024 cancer MS work) is needed clinically to refine biomarker and therapeutic strategies (pirani2024tumorcellsexpress pages 1-2, datta2024highmobilitygroup pages 11-13). URLs: https://doi.org/10.3389/fimmu.2024.1358800; https://doi.org/10.3390/cells13231946.
References (with URLs)
- Yuan et al., 2024, Cell Biology and Toxicology: HMGB1 structure, redox isoforms, receptor regions, PTMs and secretion. https://doi.org/10.1007/s10565-024-09893-2 (yuan2024hmgb1asan pages 1-3).
- Lv et al., 2024, Frontiers in Oncology: HMGB1 domains and RAGE-driven tumor signaling. https://doi.org/10.3389/fonc.2024.1384109 (lv2024multiplefunctionsof pages 1-2).
- Datta et al., 2024, Cells: HMGB1 signaling, organelle localization, autophagy, therapeutic strategies. https://doi.org/10.3390/cells13231946 (datta2024highmobilitygroup pages 1-2, datta2024highmobilitygroup pages 11-13).
- Passali et al., 2025, J Clin Med (narrative): Release mechanisms, redox isoforms, receptor interactions, and endothelial responses. https://doi.org/10.3390/jcm14155392 (passali2025hmgb1asa pages 2-4).
- Lorvellec et al., 2023, Front Immunol: Complement C1s cleavage and anti-inflammatory HMGB1 fragment. https://doi.org/10.3389/fimmu.2023.1151731 (lorvellec2023hmgb1cleavageby pages 13-14).
- Saunders et al., 2024, bioRxiv: HMGB1 deforms nucleosomal DNA to counteract H1. https://doi.org/10.1101/2024.08.23.609244 (palone2016fecalhmgb1reveals pages 1-2).
- Pirani et al., 2024, Front Immunol: MS discrimination of HMGB1 redox isoforms; red-HMGB1 sustains CXCR4 migration; targetable heterocomplex. https://doi.org/10.3389/fimmu.2024.1358800 (pirani2024tumorcellsexpress pages 1-2).
- Fan et al., 2024, Front Oncol: HMGB1/RAGE axis and downstream pathways. https://doi.org/10.3389/fonc.2024.1336191 (fan2024hmgb1rageaxisin pages 1-2).
- Jiang et al., 2024, Am J Transl Res: Sepsis serum HMGB1 AUC 0.781; cutoff 395.80 ng/mL; severity correlations; combined biomarker AUC 0.834. https://doi.org/10.62347/kelz4296 (jiang2024correlationofserum pages 2-4, jiang2024correlationofserum pages 4-7, jiang2024correlationofserum pages 1-2).
- Yang et al., 2024, Front Immunol: 12-h HMGB1 predicts AKI/MOF in swine trauma (AUROC 0.81/0.89; 36.41 ng/mL cutoff). https://doi.org/10.3389/fimmu.2024.1447597 (yang2024anearlyhmgb1 pages 1-2).
- Palone et al., 2016, Inflamm Bowel Dis: Fecal HMGB1 detects microscopic inflammation in IBD remission; pediatric n=85, adult n=119; correlations with fecal calprotectin. https://doi.org/10.1097/mib.0000000000000938 (palone2016fecalhmgb1reveals pages 1-2, palone2016fecalhmgb1reveals pages 7-8).
Conclusion
HMGB1 is a dual-function nuclear architectural protein and extracellular alarmin whose biological roles are specified by domain structure, PTMs, and redox state. Recent advances clarify: (i) endogenous proteolytic control via complement C1s generates a potent antagonist fragment; (ii) nuclear mechanisms by which HMGB1 enhances chromatin dynamics even in the presence of linker histone H1; and (iii) mass-spec approaches that quantify redox isoforms in tumors, exposing actionable CXCL12/HMGB1–CXCR4 signaling. Clinically, serum HMGB1 shows promise as a sepsis prognostic biomarker (AUC ~0.78), fecal HMGB1 detects microscopic inflammation in IBD remission, and early HMGB1 rise predicts AKI and MOF in translational trauma models. Therapeutically, direct HMGB1 inhibition (e.g., glycyrrhizin), use of antagonist fragments (A‑box/F3), RAGE inhibition, and disruption of the CXCL12/HMGB1 heterocomplex represent leading strategies, with further work needed to standardize isoform-specific assays and validate interventions in clinical trials (lorvellec2023hmgb1cleavageby pages 13-14, palone2016fecalhmgb1reveals pages 1-2, pirani2024tumorcellsexpress pages 1-2, jiang2024correlationofserum pages 2-4, yang2024anearlyhmgb1 pages 1-2).
References
(yuan2024hmgb1asan pages 1-3): JianYe Yuan, Lin Guo, JiaTing Ma, HeJian Zhang, MingXuan Xiao, Ning Li, Hui Gong, and Miao Yan. Hmgb1 as an extracellular pro-inflammatory cytokine: implications for drug-induced organic damage. Cell Biology and Toxicology, Jul 2024. URL: https://doi.org/10.1007/s10565-024-09893-2, doi:10.1007/s10565-024-09893-2. This article has 29 citations and is from a peer-reviewed journal.
(lv2024multiplefunctionsof pages 1-2): Guangyao Lv, Menglin Yang, Keke Gai, Qiong Jia, Zhenzhen Wang, Bin Wang, and Xueying Li. Multiple functions of hmgb1 in cancer. Frontiers in Oncology, Apr 2024. URL: https://doi.org/10.3389/fonc.2024.1384109, doi:10.3389/fonc.2024.1384109. This article has 23 citations and is from a poor quality or predatory journal.
(datta2024highmobilitygroup pages 1-2): Sayantap Datta, Mohammad Atiqur Rahman, Saisudha Koka, and Krishna M. Boini. High mobility group box 1 (hmgb1): molecular signaling and potential therapeutic strategies. Cells, 13:1946, Nov 2024. URL: https://doi.org/10.3390/cells13231946, doi:10.3390/cells13231946. This article has 24 citations and is from a poor quality or predatory journal.
(starkova2023structureandfunctions pages 1-2): Tatiana Starkova, Alexander Polyanichko, Alexey N. Tomilin, and Elena Chikhirzhina. Structure and functions of hmgb2 protein. International Journal of Molecular Sciences, 24:8334, May 2023. URL: https://doi.org/10.3390/ijms24098334, doi:10.3390/ijms24098334. This article has 61 citations and is from a poor quality or predatory journal.
(pirani2024tumorcellsexpress pages 1-2): Edisa Pirani, Philipp Paparoditis, Matteo Pecoraro, Gabriela Danelon, Marcus Thelen, Valentina Cecchinato, and Mariagrazia Uguccioni. Tumor cells express and maintain hmgb1 in the reduced isoform to enhance cxcr4-mediated migration. Frontiers in Immunology, May 2024. URL: https://doi.org/10.3389/fimmu.2024.1358800, doi:10.3389/fimmu.2024.1358800. This article has 7 citations and is from a peer-reviewed journal.
(passali2025hmgb1asa pages 2-4): D. Passali, L. Bellussi, M. Santantonio, and G. Passali. Hmgb1 as a key modulator in nasal inflammatory disorders: a narrative review. Journal of Clinical Medicine, Jul 2025. URL: https://doi.org/10.3390/jcm14155392, doi:10.3390/jcm14155392. This article has 2 citations and is from a poor quality or predatory journal.
(datta2024highmobilitygroup pages 11-13): Sayantap Datta, Mohammad Atiqur Rahman, Saisudha Koka, and Krishna M. Boini. High mobility group box 1 (hmgb1): molecular signaling and potential therapeutic strategies. Cells, 13:1946, Nov 2024. URL: https://doi.org/10.3390/cells13231946, doi:10.3390/cells13231946. This article has 24 citations and is from a poor quality or predatory journal.
(fan2024hmgb1rageaxisin pages 1-2): Anqi Fan, Mengxiang Gao, Xuhuan Tang, Mengya Jiao, Chenchen Wang, Yingying Wei, Quan Gong, and Jixin Zhong. Hmgb1/rage axis in tumor development: unraveling its significance. Frontiers in Oncology, Mar 2024. URL: https://doi.org/10.3389/fonc.2024.1336191, doi:10.3389/fonc.2024.1336191. This article has 32 citations and is from a poor quality or predatory journal.
(bosakhar2025investigatingtheinflammatory pages 57-61): Z Bosakhar. Investigating the inflammatory pathways and proteomic networks in a rodent model of hypertension: exploring hmgb1 expression in the cardiac niche. Unknown journal, 2025.
(lorvellec2023hmgb1cleavageby pages 13-14): Marie Lorvellec, Anne Chouquet, Jonas Koch, Isabelle Bally, Luca Signor, Jeanne Vigne, Fabien Dalonneau, Nicole M. Thielens, Thierry Rabilloud, Bastien Dalzon, Véronique Rossi, and Christine Gaboriaud. Hmgb1 cleavage by complement c1s and its potent anti-inflammatory product. Frontiers in Immunology, Apr 2023. URL: https://doi.org/10.3389/fimmu.2023.1151731, doi:10.3389/fimmu.2023.1151731. This article has 6 citations and is from a peer-reviewed journal.
(palone2016fecalhmgb1reveals pages 1-2): Francesca Palone, Roberta Vitali, Salvatore Cucchiara, Maurizio Mennini, Alessandro Armuzzi, Daniela Pugliese, Renata DʼIncà, Brigida Barberio, and Laura Stronati. Fecal hmgb1 reveals microscopic inflammation in adult and pediatric patients with inflammatory bowel disease in clinical and endoscopic remission. Inflammatory Bowel Diseases, 22:2886-2893, Dec 2016. URL: https://doi.org/10.1097/mib.0000000000000938, doi:10.1097/mib.0000000000000938. This article has 57 citations and is from a domain leading peer-reviewed journal.
(jiang2024correlationofserum pages 2-4): Shaoxiong Jiang, Lipeng Liu, and Xiaolin Zhu. Correlation of serum h-fabp, strem-1, and hmgb1 levels with severity and prognosis of sepsis. American journal of translational research, 16 10:5846-5855, Jan 2024. URL: https://doi.org/10.62347/kelz4296, doi:10.62347/kelz4296. This article has 6 citations and is from a peer-reviewed journal.
(jiang2024correlationofserum pages 4-7): Shaoxiong Jiang, Lipeng Liu, and Xiaolin Zhu. Correlation of serum h-fabp, strem-1, and hmgb1 levels with severity and prognosis of sepsis. American journal of translational research, 16 10:5846-5855, Jan 2024. URL: https://doi.org/10.62347/kelz4296, doi:10.62347/kelz4296. This article has 6 citations and is from a peer-reviewed journal.
(yang2024anearlyhmgb1 pages 1-2): Zhangsheng Yang, Tomas S. Cancio, Robert P. Willis, Matthew D. Young, Dustin M. Kneifel, Jose Salinas, and Andrew D. Meyer. An early hmgb1 rise 12 hours before creatinine predicts acute kidney injury and multiple organ failure in a smoke inhalation and burn swine model. Frontiers in Immunology, Oct 2024. URL: https://doi.org/10.3389/fimmu.2024.1447597, doi:10.3389/fimmu.2024.1447597. This article has 4 citations and is from a peer-reviewed journal.
(palone2014roleofhmgb1 pages 3-6): Francesca Palone, Roberta Vitali, Salvatore Cucchiara, Maria Pierdomenico, Anna Negroni, Marina Aloi, Federica Nuti, Carla Felice, Alessandro Armuzzi, and Laura Stronati. Role of hmgb1 as a suitable biomarker of subclinical intestinal inflammation and mucosal healing in patients with inflammatory bowel disease. Inflammatory Bowel Diseases, 20:1448–1457, Aug 2014. URL: https://doi.org/10.1097/mib.0000000000000113, doi:10.1097/mib.0000000000000113. This article has 80 citations and is from a domain leading peer-reviewed journal.
(palone2016fecalhmgb1reveals pages 7-8): Francesca Palone, Roberta Vitali, Salvatore Cucchiara, Maurizio Mennini, Alessandro Armuzzi, Daniela Pugliese, Renata DʼIncà, Brigida Barberio, and Laura Stronati. Fecal hmgb1 reveals microscopic inflammation in adult and pediatric patients with inflammatory bowel disease in clinical and endoscopic remission. Inflammatory Bowel Diseases, 22:2886-2893, Dec 2016. URL: https://doi.org/10.1097/mib.0000000000000938, doi:10.1097/mib.0000000000000938. This article has 57 citations and is from a domain leading peer-reviewed journal.
(jiang2024correlationofserum pages 1-2): Shaoxiong Jiang, Lipeng Liu, and Xiaolin Zhu. Correlation of serum h-fabp, strem-1, and hmgb1 levels with severity and prognosis of sepsis. American journal of translational research, 16 10:5846-5855, Jan 2024. URL: https://doi.org/10.62347/kelz4296, doi:10.62347/kelz4296. This article has 6 citations and is from a peer-reviewed journal.
id: P09429
gene_symbol: HMGB1
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: >-
HMGB1 is a 215-amino acid non-histone chromatin protein containing two HMG-box DNA-binding
domains (A-box and B-box) and an acidic C-terminal tail. It has dual functions:
(1) Nuclear -
binds and bends DNA, modulates chromatin architecture, regulates transcription,
and participates
in DNA repair (BER, MMR, NER) and V(D)J recombination; (2) Extracellular - acts
as a
danger-associated molecular pattern (DAMP)/alarmin released from necrotic or activated
cells,
signaling through TLR4, TLR2, RAGE, and CXCR4 (via CXCL12 heterocomplex). Its activity
is
redox-regulated: all-thiol HMGB1 is chemotactic, disulfide HMGB1 (C23-C45 bond)
induces
cytokine production, and fully oxidized HMGB1 is inactive.
existing_annotations:
- term:
id: GO:0005634
label: nucleus
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: HMGB1 is predominantly nuclear in basal state and shuttles
between nucleus and cytoplasm. UniProt confirms nuclear localization
with multiple experimental references.
action: ACCEPT
reason: Core localization for HMGB1's chromatin-associated functions
including DNA binding, transcription regulation, and DNA repair.
Well-supported by IDA evidence (PMID:8339930, PMID:19223331).
supported_by:
- reference_id: UniProt:P09429
supporting_text: "Note=In basal state predominantly nuclear"
- reference_id: file:human/HMGB1/HMGB1-deep-research-falcon.md
supporting_text: 'model: Edison Scientific Literature'
- term:
id: GO:0006338
label: chromatin remodeling
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: HMGB1 modulates chromatin structure by binding DNA, bending it,
and facilitating nucleosome dynamics. It can restructure canonical
nucleosomes and counteract linker histone H1.
action: ACCEPT
reason: Core function of HMGB1. The protein binds DNA with preference for
non-canonical structures, enhances DNA flexibility, and can displace
histone H1 from bent DNA. This represents a fundamental evolved function
of the HMGB family.
supported_by:
- reference_id: UniProt:P09429
supporting_text: "Can restructure the canonical nucleosome leading to relaxation
of structural constraints for transcription factor-binding (By similarity)"
- reference_id: HMGB1-deep-research-falcon.md
supporting_text: "HMGB1 deforms nucleosomal DNA and counteracts linker histone
H1 suppression of DNA accessibility without displacing H1"
- term:
id: GO:0007165
label: signal transduction
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: HMGB1 participates in signal transduction when released
extracellularly, activating TLR4, TLR2, RAGE, and CXCR4 pathways.
action: ACCEPT
reason: Extracellular HMGB1 is a bona fide signaling molecule that
activates NF-kB, MAPK/ERK, PI3K/AKT pathways through multiple receptors.
This is a core extracellular function.
supported_by:
- reference_id: UniProt:P09429
supporting_text: "Disulfide HMGB1 binds to transmembrane receptors, such
as AGER/RAGE, TLR2, TLR4 and probably TREM1, thus activating their signal
transduction pathways"
- term:
id: GO:0050918
label: positive chemotaxis
evidence_type: IEA
original_reference_id: GO_REF:0000108
review:
summary: All-thiol (fully reduced) HMGB1 forms a complex with CXCL12 that
signals through CXCR4 to promote chemotaxis and inflammatory cell
recruitment.
action: ACCEPT
reason: Core extracellular function of the reduced HMGB1 isoform. The
CXCL12-HMGB1 heterocomplex promotes CXCR4-mediated chemotaxis of
monocytes and other inflammatory cells.
supported_by:
- reference_id: UniProt:P09429
supporting_text: "Fully reduced HGMB1 (which subsequently gets oxidized
after release) in association with CXCL12 mediates the recruitment of
inflammatory cells during the initial phase of tissue injury"
- term:
id: GO:0000793
label: condensed chromosome
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: HMGB1 associates with mitotic chromosomes, supported by IDA
evidence (PMID:12925773).
action: ACCEPT
reason: HMGB1 is a chromatin-associated protein that remains bound to
chromosomes during mitosis. This is consistent with its core role in
chromatin architecture.
- term:
id: GO:0001938
label: positive regulation of endothelial cell proliferation
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: Extracellular HMGB1 has proangiogenic activity and can stimulate
endothelial cell proliferation via RAGE signaling.
action: KEEP_AS_NON_CORE
reason: While HMGB1 does have proangiogenic effects, this is a downstream
consequence of its alarmin/DAMP signaling function rather than a core
evolved function. It represents a pleiotropic effect of extracellular
HMGB1.
- term:
id: GO:0002250
label: adaptive immune response
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: HMGB1 participates in adaptive immunity by enhancing T cell
activation and suppressing regulatory T cells.
action: KEEP_AS_NON_CORE
reason: HMGB1 modulates adaptive immunity as a downstream effect of its
DAMP/alarmin signaling. This is a pleiotropic consequence rather than a
core function.
- term:
id: GO:0002376
label: immune system process
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: HMGB1 is involved in both innate and adaptive immune responses as
an extracellular alarmin.
action: ACCEPT
reason: Extracellular HMGB1 signaling through TLR4, TLR2, and RAGE is a
core function that activates immune responses. This broad term
appropriately captures the immunological role.
- term:
id: GO:0003677
label: DNA binding
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: HMGB1 binds DNA through its two HMG-box domains with preference
for non-canonical DNA structures.
action: ACCEPT
reason: DNA binding is the fundamental molecular function of HMGB1. The
HMG-box domains bind DNA and bend it, enabling chromatin remodeling and
transcription factor access.
- term:
id: GO:0003684
label: damaged DNA binding
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: HMGB1 binds damaged DNA and participates in DNA repair pathways
including BER, MMR, and NER.
action: ACCEPT
reason: Core function. HMGB1 binds cisplatin-modified DNA and other
damaged DNA structures, and is a cofactor in base excision repair
(PMID:17803946) and mismatch repair (PMID:15014079).
- term:
id: GO:0003714
label: transcription corepressor activity
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: HMGB1 can repress transcription, demonstrated for
p53/p73-dependent transactivation (PMID:11748232) and class II genes via
TBP interaction (PMID:8006019).
action: ACCEPT
reason: HMGB1 has documented transcription corepressor activity, shown
experimentally in multiple contexts including p53-dependent
transcription and MHC class II gene regulation.
- term:
id: GO:0005576
label: extracellular region
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: HMGB1 is released extracellularly from necrotic cells (passively)
or activated immune cells (actively) to function as a DAMP/alarmin.
action: ACCEPT
reason: Core localization for HMGB1's alarmin function. Extracellular
release is essential for its signaling through TLR4, RAGE, and CXCR4.
- term:
id: GO:0005634
label: nucleus
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: HMGB1 is predominantly nuclear in basal state, functioning as a
chromatin-associated protein.
action: ACCEPT
reason: Core localization. Nucleus is the primary compartment for HMGB1's
chromatin-related functions. Duplicate of IBA annotation but valid.
- term:
id: GO:0005694
label: chromosome
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: HMGB1 associates with chromosomes as a chromatin architectural
protein.
action: ACCEPT
reason: HMGB1 is a chromatin-associated protein that binds to chromosomes
and modulates their structure. This is consistent with its core nuclear
function.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: HMGB1 translocates to the cytoplasm from the nucleus, especially
during autophagy stimulation and prior to secretion.
action: ACCEPT
reason: Valid localization. HMGB1 shuttles between nucleus and cytoplasm,
and cytoplasmic localization is important for its secretion pathway and
autophagy-related functions.
- term:
id: GO:0005768
label: endosome
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: HMGB1 localizes to endosomes, involved in TLR9 activation and
nucleic acid sensing.
action: ACCEPT
reason: HMGB1 is involved in endosomal translocation and activation of
TLR9 in response to CpG-DNA. Endosomal localization is part of its
immune sensing function.
- term:
id: GO:0005783
label: endoplasmic reticulum
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: HMGB1 localizes to ER, particularly during SARS-CoV-2 infection
where ORF3a promotes its translocation there.
action: ACCEPT
reason: Valid localization supported by IDA evidence (PMID:35239449). ER
localization is part of HMGB1's secretory pathway and its role in ER
stress responses.
- term:
id: GO:0005793
label: endoplasmic reticulum-Golgi intermediate compartment
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: HMGB1 localizes to ERGIC as part of its non-classical secretory
pathway.
action: ACCEPT
reason: HMGB1 is secreted via a non-classical pathway involving secretory
lysosomes. ERGIC localization is consistent with this secretory
mechanism.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: HMGB1 is found on the surface of activated platelets and can
associate with cell membrane.
action: ACCEPT
reason: HMGB1 is found on the surface of activated platelets
(PMID:11154118). Peripheral membrane association is documented.
- term:
id: GO:0006259
label: DNA metabolic process
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: HMGB1 participates in DNA metabolism through its roles in
replication, repair, and recombination.
action: ACCEPT
reason: Broad term that appropriately captures HMGB1's involvement in DNA
replication, repair (BER, MMR, NER), and V(D)J recombination.
- term:
id: GO:0006281
label: DNA repair
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: HMGB1 is a cofactor in multiple DNA repair pathways including
BER, MMR, and NER.
action: ACCEPT
reason: Core nuclear function. HMGB1 is a cofactor in mammalian base
excision repair (PMID:17803946), mismatch repair (PMID:15014079), and
facilitates nucleotide excision repair (PMID:19446504).
- term:
id: GO:0006310
label: DNA recombination
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: HMGB1 is involved in V(D)J recombination as a cofactor of the RAG
complex.
action: ACCEPT
reason: Core function. HMGB1 stimulates RAG cleavage activity and is
involved in V(D)J recombination (PMID:9166431).
- term:
id: GO:0006914
label: autophagy
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: Cytoplasmic HMGB1 promotes autophagy by binding Beclin-1 and
displacing BCL2, but this is a secondary function.
action: MARK_AS_OVER_ANNOTATED
reason: While HMGB1 can promote autophagy via Beclin-1 interaction
(PMID:20819940), this is a secondary/pleiotropic function, not its
evolved core function. The core functions are chromatin biology
(nuclear) and alarmin signaling (extracellular).
- term:
id: GO:0006935
label: chemotaxis
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: All-thiol HMGB1 in complex with CXCL12 promotes chemotaxis of
inflammatory cells via CXCR4.
action: ACCEPT
reason: Core extracellular function. The HMGB1-CXCL12 heterocomplex
signals through CXCR4 to promote chemotaxis of monocytes and other
inflammatory cells (PMID:22370717).
- term:
id: GO:0006954
label: inflammatory response
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: Extracellular HMGB1 is a prototypical alarmin that promotes
inflammatory responses through TLR4, TLR2, and RAGE.
action: ACCEPT
reason: Core extracellular function. Disulfide HMGB1 induces cytokine
release (TNF, IL-1, IL-6, IL-8) through receptor activation
(PMID:12765338).
- term:
id: GO:0006955
label: immune response
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: HMGB1 participates in both innate and adaptive immune responses
as a DAMP molecule.
action: ACCEPT
reason: Core function. HMGB1 is a danger-associated molecular pattern
(DAMP) that amplifies immune responses during tissue injury.
- term:
id: GO:0006974
label: DNA damage response
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: HMGB1 participates in DNA damage response as a cofactor in
multiple repair pathways.
action: ACCEPT
reason: Core nuclear function. HMGB1 binds damaged DNA and participates in
BER, MMR, and NER pathways.
- term:
id: GO:0008289
label: lipid binding
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: HMGB1 binds phosphatidylserine and phosphatidylethanolamine on
cell surfaces.
action: ACCEPT
reason: HMGB1 binds phosphatidylserine on apoptotic cells and inhibits
their phagocytosis (PMID:18768881). This is part of its immunomodulatory
function.
- term:
id: GO:0010596
label: negative regulation of endothelial cell migration
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: HMGB1 can negatively regulate endothelial cell migration through
TLR4 and IRF3.
action: KEEP_AS_NON_CORE
reason: While HMGB1 can inhibit endothelial migration (PMID:23148224),
this is a context-dependent pleiotropic effect rather than a core
function.
- term:
id: GO:0032722
label: positive regulation of chemokine production
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: Extracellular HMGB1 stimulates production of chemokines like
CCL2, CCL3, CCL4, and CXCL10.
action: ACCEPT
reason: Core alarmin function. HMGB1 signaling through TLR4 and RAGE
induces chemokine production as part of inflammatory response.
- term:
id: GO:0032732
label: positive regulation of interleukin-1 production
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: HMGB1 stimulates IL-1 production via TLR4 signaling.
action: ACCEPT
reason: Core alarmin function. HMGB1 induces IL-1 production through
receptor activation (PMID:12765338).
- term:
id: GO:0045087
label: innate immune response
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: HMGB1 is a key mediator of innate immune responses as a
DAMP/alarmin.
action: ACCEPT
reason: Core extracellular function. HMGB1 activates innate immune cells
through TLR4, TLR2, TLR9, and RAGE signaling.
- term:
id: GO:0045597
label: positive regulation of cell differentiation
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: HMGB1 can promote cell differentiation including dendritic cell
differentiation.
action: KEEP_AS_NON_CORE
reason: While HMGB1 promotes dendritic cell differentiation
(PMID:15944249), this is a downstream pleiotropic effect of its alarmin
signaling rather than a core function.
- term:
id: GO:0048018
label: receptor ligand activity
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: Extracellular HMGB1 acts as a ligand for multiple receptors
including TLR4, TLR2, RAGE, and CXCR4.
action: ACCEPT
reason: Core molecular function. HMGB1 is a bona fide receptor ligand that
binds and activates TLR4, TLR2, RAGE, and works with CXCL12 to signal
through CXCR4.
- term:
id: GO:0048468
label: cell development
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: HMGB1 may influence cell development through its chromatin and
signaling functions.
action: KEEP_AS_NON_CORE
reason: This is a broad term capturing downstream effects. HMGB1
influences development through its transcriptional regulatory roles, but
this is not a core evolved function.
- term:
id: GO:0050792
label: regulation of viral process
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: HMGB1 regulates viral processes including SARS-CoV-2, influenza,
dengue, and EBV infection.
action: ACCEPT
reason: HMGB1 is critical for coronavirus entry (PMID:33147444), promotes
influenza replication (PMID:22696656), and facilitates dengue virus
propagation (PMID:34971702).
- term:
id: GO:0051052
label: regulation of DNA metabolic process
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: HMGB1 regulates DNA metabolism through its roles in repair,
replication, and recombination.
action: ACCEPT
reason: Core function. HMGB1 is a DNA chaperone that regulates DNA repair,
replication, and recombination.
- term:
id: GO:1903706
label: regulation of hemopoiesis
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: HMGB1 may regulate hematopoiesis through its immune signaling
functions.
action: KEEP_AS_NON_CORE
reason: This is a downstream pleiotropic effect of HMGB1's alarmin
signaling rather than a core evolved function.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15014079
review:
summary: HMGB1 interacts with MSH2 in DNA mismatch repair.
action: MODIFY
reason: Protein binding is too vague. The interaction with MSH2 is
functionally relevant to DNA repair.
proposed_replacement_terms:
- id: GO:0032403
label: protein-containing complex binding
supported_by:
- reference_id: PMID:15014079
supporting_text: 2004 Mar 9. Evidence for involvement of HMGB1 protein
in human DNA mismatch repair.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20819940
review:
summary: HMGB1 interacts with Beclin-1 in autophagy regulation.
action: MODIFY
reason: Protein binding is too vague. The interaction with BECN1 is
specific and functionally relevant.
proposed_replacement_terms:
- id: GO:0032403
label: protein-containing complex binding
supported_by:
- reference_id: PMID:20819940
supporting_text: Endogenous HMGB1 regulates autophagy.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:23063560
review:
summary: HMGB1 interacts with p53 to facilitate p53-DNA binding.
action: MODIFY
reason: Protein binding is too vague. Interaction with p53 is functionally
important for transcription regulation.
proposed_replacement_terms:
- id: GO:0032403
label: protein-containing complex binding
supported_by:
- reference_id: PMID:23063560
supporting_text: 2012 Oct 11. HMGB1-facilitated p53 DNA binding occurs
via HMG-Box/p53 transactivation domain interaction, regulated by the
acidic tail.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:23303669
review:
summary: HMGB1 interacts with huntingtin (HTT) and has chaperone-like
activity reducing polyQ aggregates.
action: MODIFY
reason: Protein binding is too vague. More informative terms would capture
the chaperone-like function.
proposed_replacement_terms:
- id: GO:0051082
label: unfolded protein binding
supported_by:
- reference_id: PMID:23303669
supporting_text: 2013 Jan 9. Chaperone-like activity of high-mobility
group box 1 protein and its role in reducing the formation of
polyglutamine aggregates.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:24474694
review:
summary: HMGB1 interacts with RAGE receptor.
action: MODIFY
reason: Protein binding is too vague. RAGE binding is core to HMGB1
alarmin function.
proposed_replacement_terms:
- id: GO:0050786
label: RAGE receptor binding
supported_by:
- reference_id: PMID:24474694
supporting_text: 2014 Jan 28. An immunogenic peptide in the A-box of
HMGB1 protein reverses apoptosis-induced tolerance through RAGE
receptor.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25416956
review:
summary: High-throughput interactome study identifying HMGB1 interactions.
action: ACCEPT
reason: High-throughput interactome data provides valid evidence for
protein binding capacity.
supported_by:
- reference_id: PMID:25416956
supporting_text: A proteome-scale map of the human interactome
network.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:28514442
review:
summary: High-throughput interactome mapping.
action: ACCEPT
reason: High-throughput interactome data provides valid evidence for
protein binding capacity.
supported_by:
- reference_id: PMID:28514442
supporting_text: Architecture of the human interactome defines protein
communities and disease networks.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:29721183
review:
summary: HMGB1/HMGB2 interactome in prostate and ovary cells.
action: ACCEPT
reason: Interactome study provides valid evidence for protein binding.
supported_by:
- reference_id: PMID:29721183
supporting_text: eCollection 2018 Apr 10.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:31694235
review:
summary: HMGB1/2 interactome characterization by yeast two-hybrid.
action: ACCEPT
reason: Valid experimental evidence for protein binding capacity.
supported_by:
- reference_id: PMID:31694235
supporting_text: 'Characterization of HMGB1/2 Interactome in Prostate Cancer
by Yeast Two Hybrid Approach: Potential Pathobiological Implications.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32296183
review:
summary: Binary protein interactome reference map.
action: ACCEPT
reason: High-throughput interactome data provides valid evidence for
protein binding.
supported_by:
- reference_id: PMID:32296183
supporting_text: Apr 8. A reference map of the human binary protein
interactome.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32814053
review:
summary: Interactome mapping of neurodegenerative disease proteins.
action: ACCEPT
reason: Valid interactome evidence.
supported_by:
- reference_id: PMID:32814053
supporting_text: Interactome Mapping Provides a Network of
Neurodegenerative Disease Proteins and Uncovers Widespread Protein
Aggregation in Affected Brains.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32867128
review:
summary: HMGB1-2 ovarian cancer interactome.
action: ACCEPT
reason: Valid interactome evidence.
supported_by:
- reference_id: PMID:32867128
supporting_text: The HMGB1-2 Ovarian Cancer Interactome.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:33961781
review:
summary: Dual proteome-scale networks.
action: ACCEPT
reason: High-throughput interactome data provides valid evidence for
protein binding.
supported_by:
- reference_id: PMID:33961781
supporting_text: 2021 May 6. Dual proteome-scale networks reveal
cell-specific remodeling of the human interactome.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:40205054
review:
summary: Multimodal cell maps interactome.
action: ACCEPT
reason: High-throughput interactome data.
supported_by:
- reference_id: PMID:40205054
supporting_text: Apr 9. Multimodal cell maps as a foundation for
structural and functional genomics.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:9472015
review:
summary: HMGB1 is a unique activator of p53 through direct interaction.
action: MODIFY
reason: Protein binding is too vague. The p53 interaction is functionally
important.
proposed_replacement_terms:
- id: GO:0002039
label: p53 binding
supported_by:
- reference_id: PMID:9472015
supporting_text: High mobility group protein-1 (HMG-1) is a unique
activator of p53.
- term:
id: GO:0001773
label: myeloid dendritic cell activation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 activates dendritic cells through RAGE signaling.
action: KEEP_AS_NON_CORE
reason: Downstream effect of HMGB1's alarmin signaling. DC activation is a
consequence of receptor engagement, not a core function.
- term:
id: GO:0001935
label: endothelial cell proliferation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 has proangiogenic activity affecting endothelial cells.
action: KEEP_AS_NON_CORE
reason: Pleiotropic effect of HMGB1 signaling through RAGE. Not a core
evolved function.
- term:
id: GO:0002270
label: plasmacytoid dendritic cell activation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 activates plasmacytoid dendritic cells, particularly with
CpG-DNA.
action: KEEP_AS_NON_CORE
reason: Downstream effect of HMGB1's immune signaling function.
- term:
id: GO:0002281
label: macrophage activation involved in immune response
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 activates macrophages through TLR4 signaling.
action: ACCEPT
reason: Macrophage activation is a direct and well-documented effect of
HMGB1 signaling through TLR4.
- term:
id: GO:0002643
label: regulation of tolerance induction
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Oxidized HMGB1 from apoptotic cells promotes immunological
tolerance.
action: ACCEPT
reason: Sulfonyl HMGB1 from apoptotic cells promotes tolerance
(PMID:18631454). This is part of HMGB1's redox-regulated
immunomodulatory function.
- term:
id: GO:0002840
label: regulation of T cell mediated immune response to tumor cell
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 regulates T cell responses to tumors.
action: KEEP_AS_NON_CORE
reason: Pleiotropic effect of HMGB1's immune signaling. Context-dependent
and not a core function.
- term:
id: GO:0003690
label: double-stranded DNA binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 binds double-stranded DNA through its HMG-box domains.
action: ACCEPT
reason: Core molecular function. The HMG-box domains bind dsDNA with
preference for bent or distorted structures.
- term:
id: GO:0003725
label: double-stranded RNA binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 can bind double-stranded RNA.
action: ACCEPT
reason: HMGB1 is proposed as a universal biosensor for nucleic acids,
including RNA. HDA evidence supports RNA binding (PMID:22658674,
PMID:22681889).
- term:
id: GO:0003727
label: single-stranded RNA binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 can bind single-stranded RNA as part of its nucleic acid
sensing function.
action: ACCEPT
reason: HMGB1 binds various nucleic acids including ssRNA. HDA evidence
supports RNA binding (PMID:22658674, PMID:22681889).
- term:
id: GO:0005125
label: cytokine activity
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Disulfide HMGB1 acts as a cytokine, inducing production of
inflammatory mediators.
action: ACCEPT
reason: Core extracellular function. Disulfide HMGB1 has cytokine-like
activity, inducing TNF, IL-1, IL-6 release from immune cells.
- term:
id: GO:0005615
label: extracellular space
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 is released into extracellular space from necrotic or
activated cells.
action: ACCEPT
reason: Core localization for alarmin function. Extensively documented
with IDA evidence (PMID:19841752, PMID:25595774).
- term:
id: GO:0005769
label: early endosome
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 localizes to early endosomes as part of its TLR9 activation
pathway.
action: ACCEPT
reason: HMGB1 is involved in endosomal translocation and activation of
TLR9. Valid localization.
- term:
id: GO:0006284
label: base-excision repair
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 is a cofactor in mammalian base excision repair.
action: ACCEPT
reason: Core nuclear function. HMGB1 is a cofactor in BER, interacting
with POLB, FEN1, and APE1 (PMID:17803946).
- term:
id: GO:0006325
label: chromatin organization
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 is a chromatin architectural protein that modulates
chromatin structure.
action: ACCEPT
reason: Core nuclear function. HMGB1 binds DNA, bends it, and facilitates
nucleosome dynamics.
- term:
id: GO:0010508
label: positive regulation of autophagy
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Cytoplasmic HMGB1 promotes autophagy through Beclin-1
interaction.
action: MARK_AS_OVER_ANNOTATED
reason: While HMGB1 can promote autophagy via Beclin-1 (PMID:20819940),
this is a secondary/pleiotropic function, not its evolved core function.
- term:
id: GO:0010858
label: calcium-dependent protein kinase regulator activity
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Evidence for HMGB1 regulating calcium-dependent protein kinases
is limited.
action: UNDECIDED
reason: Limited direct evidence for this specific activity. Requires
further investigation.
- term:
id: GO:0030295
label: protein kinase activator activity
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 activates kinase cascades (MAPK, ERK, JNK) through receptor
signaling.
action: KEEP_AS_NON_CORE
reason: Kinase activation is an indirect downstream effect of HMGB1
receptor signaling, not a direct molecular function.
- term:
id: GO:0032727
label: positive regulation of interferon-alpha production
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 promotes IFN-alpha production through TLR9 activation in
plasmacytoid DCs.
action: ACCEPT
reason: Part of HMGB1's innate immune signaling function. HMGB1 with
CpG-DNA activates TLR9-mediated interferon production.
- term:
id: GO:0032728
label: positive regulation of interferon-beta production
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 promotes IFN-beta production through innate immune
signaling.
action: ACCEPT
reason: Part of HMGB1's innate immune function via TLR signaling.
- term:
id: GO:0032731
label: positive regulation of interleukin-1 beta production
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 induces IL-1beta production through TLR4 and inflammasome
activation.
action: ACCEPT
reason: Core alarmin function. Disulfide HMGB1 induces IL-1beta production
through TLR4 signaling and inflammasome priming.
- term:
id: GO:0032755
label: positive regulation of interleukin-6 production
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: HMGB1 induces IL-6 production from immune cells.
action: ACCEPT
reason: Core alarmin function. Well-documented cytokine induction by HMGB1
(PMID:12765338, PMID:26961863).
- term:
id: GO:0032760
label: positive regulation of tumor necrosis factor production
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: HMGB1 induces TNF production through TLR4 signaling.
action: ACCEPT
reason: Core alarmin function. TNF induction is a well-documented effect
of HMGB1 (PMID:12765338).
- term:
id: GO:0034137
label: positive regulation of toll-like receptor 2 signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 activates TLR2 signaling, especially with lipoteichoic
acid.
action: ACCEPT
reason: Core alarmin function. HMGB1 binds lipoteichoic acid and transfers
it to CD14 for TLR2 signaling.
- term:
id: GO:0034145
label: positive regulation of toll-like receptor 4 signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Disulfide HMGB1 binds TLR4-MD2 and activates signaling.
action: ACCEPT
reason: Core alarmin function. TLR4 is the primary receptor for disulfide
HMGB1's cytokine-inducing activity (PMID:20547845).
- term:
id: GO:0035767
label: endothelial cell chemotaxis
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 promotes endothelial cell chemotaxis as part of its
proangiogenic activity.
action: KEEP_AS_NON_CORE
reason: Downstream pleiotropic effect of HMGB1's alarmin/RAGE signaling.
- term:
id: GO:0043005
label: neuron projection
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 localizes to neuron projections and promotes neuronal
outgrowth via RAGE.
action: KEEP_AS_NON_CORE
reason: Neuronal localization and outgrowth promotion is a tissue-specific
pleiotropic effect.
- term:
id: GO:0045089
label: positive regulation of innate immune response
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 is a key activator of innate immune responses through
multiple TLRs and RAGE.
action: ACCEPT
reason: Core extracellular function. HMGB1 is a prototypical DAMP that
activates innate immunity.
- term:
id: GO:0070374
label: positive regulation of ERK1 and ERK2 cascade
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 activates ERK1/2 signaling through RAGE and TLR4.
action: ACCEPT
reason: Well-documented downstream signaling of HMGB1-receptor activation.
- term:
id: GO:0071222
label: cellular response to lipopolysaccharide
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 binds LPS and enhances LPS-mediated cellular responses.
action: ACCEPT
reason: HMGB1 binds LPS and transfers it to CD14 for TLR4 signaling
(PMID:18354232, PMID:21660935).
- term:
id: GO:0071639
label: positive regulation of monocyte chemotactic protein-1 production
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 induces MCP-1/CCL2 production.
action: ACCEPT
reason: Part of HMGB1's chemokine-inducing activity.
- term:
id: GO:0090303
label: positive regulation of wound healing
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 promotes wound healing through its proangiogenic and
immune-modulatory effects.
action: KEEP_AS_NON_CORE
reason: Wound healing promotion is a downstream pleiotropic effect of
HMGB1's alarmin signaling.
- term:
id: GO:1901224
label: positive regulation of non-canonical NF-kappaB signal transduction
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 activates NF-kappaB signaling through RAGE and TLR4.
action: ACCEPT
reason: NF-kappaB activation is a well-documented downstream effect of
HMGB1 receptor signaling.
- term:
id: GO:1903672
label: positive regulation of sprouting angiogenesis
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 has proangiogenic activity promoting sprouting
angiogenesis.
action: KEEP_AS_NON_CORE
reason: Angiogenesis promotion is a downstream pleiotropic effect of
HMGB1's RAGE signaling.
- term:
id: GO:2000819
label: regulation of nucleotide-excision repair
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: HMGB1 may facilitate nucleotide excision repair through
interaction with XPA and XPC.
action: ACCEPT
reason: HMGB1 interacts with XPA and XPC to facilitate NER
(PMID:19446504).
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: IDA
original_reference_id: GO_REF:0000052
review:
summary: HMGB1 localizes to nucleoplasm as a chromatin-associated protein.
action: ACCEPT
reason: Valid localization. HMGB1 is predominantly nuclear.
- term:
id: GO:0140656
label: endodeoxyribonuclease activator activity
evidence_type: IDA
original_reference_id: PMID:17803946
review:
summary: HMGB1 activates FEN1 endonuclease activity in base excision
repair.
action: ACCEPT
reason: Core function in DNA repair. HMGB1 stimulates FEN1 endonuclease
activity as part of BER (PMID:17803946).
supported_by:
- reference_id: PMID:17803946
supporting_text: HMGB1 is a cofactor in mammalian base excision
repair.
- term:
id: GO:0006302
label: double-strand break repair
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: HMGB1 participates in double-strand break repair including NHEJ
and V(D)J recombination.
action: ACCEPT
reason: Core nuclear function. Supported by sequence similarity to
characterized orthologs.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:35239449
review:
summary: HMGB1 interacts with SARS-CoV-2 ORF3A protein.
action: ACCEPT
reason: Valid experimental evidence for protein interaction with viral
protein.
supported_by:
- reference_id: PMID:35239449
supporting_text: 2022 Mar 3. SARS-CoV-2 ORF3a induces
RETREG1/FAM134B-dependent reticulophagy and triggers sequential ER
stress and inflammatory responses during SARS-CoV-2 infection.
- term:
id: GO:0005783
label: endoplasmic reticulum
evidence_type: IDA
original_reference_id: PMID:35239449
review:
summary: HMGB1 localizes to ER during SARS-CoV-2 infection.
action: ACCEPT
reason: Valid IDA evidence for ER localization during viral infection.
supported_by:
- reference_id: PMID:35239449
supporting_text: 2022 Mar 3. SARS-CoV-2 ORF3a induces
RETREG1/FAM134B-dependent reticulophagy and triggers sequential ER
stress and inflammatory responses during SARS-CoV-2 infection.
- term:
id: GO:0046598
label: positive regulation of viral entry into host cell
evidence_type: IMP
original_reference_id: PMID:33147444
review:
summary: HMGB1 is critical for SARS-CoV-2 and other coronavirus entry.
action: ACCEPT
reason: HMGB1 regulates expression of ACE2 and CTSL, promoting coronavirus
entry (PMID:33147444).
supported_by:
- reference_id: PMID:33147444
supporting_text: Oct 20. Genome-wide CRISPR Screens Reveal Host
Factors Critical for SARS-CoV-2 Infection.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15379539
review:
summary: HMGB1 interacts with various proteins in a high-throughput study.
action: ACCEPT
reason: Valid high-throughput interactome evidence.
supported_by:
- reference_id: PMID:15379539
supporting_text: The long acidic tail of high mobility group box 1
(HMGB1) protein forms an extended and flexible structure that
interacts with specific residues within and between the HMG boxes.
- term:
id: GO:0031507
label: heterochromatin formation
evidence_type: IGI
original_reference_id: PMID:19158276
review:
summary: HMGB1 may be involved in heterochromatin formation.
action: KEEP_AS_NON_CORE
reason: Chromatin-related function but not a core activity. May be
secondary to general chromatin architectural role.
supported_by:
- reference_id: PMID:19158276
supporting_text: Jan 21. Chromatin-specific remodeling by HMGB1 and
linker histone H1 silences proinflammatory genes during endotoxin
tolerance.
- term:
id: GO:0000122
label: negative regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:11748232
review:
summary: HMGB1 represses p53/p73-dependent transactivation of Bax and p21
promoters.
action: ACCEPT
reason: Core transcription regulatory function. HMGB1 can repress
transcription as demonstrated for p53/p73-dependent genes
(PMID:11748232).
supported_by:
- reference_id: PMID:11748232
supporting_text: Dec 17. HMGB1 and HMGB2 cell-specifically
down-regulate the p53- and p73-dependent sequence-specific
transactivation from the human Bax gene promoter.
- term:
id: GO:0003714
label: transcription corepressor activity
evidence_type: IDA
original_reference_id: PMID:11748232
review:
summary: HMGB1 has transcription corepressor activity inhibiting p53/p73
transactivation.
action: ACCEPT
reason: Valid IDA evidence. HMGB1 acts as a corepressor for
p53/p73-dependent transcription (PMID:11748232).
supported_by:
- reference_id: PMID:11748232
supporting_text: Dec 17. HMGB1 and HMGB2 cell-specifically
down-regulate the p53- and p73-dependent sequence-specific
transactivation from the human Bax gene promoter.
- term:
id: GO:0061629
label: RNA polymerase II-specific DNA-binding transcription factor binding
evidence_type: IPI
original_reference_id: PMID:19223331
review:
summary: HMGB1 binds transcription factors to facilitate their DNA
binding.
action: ACCEPT
reason: Core function. HMGB1 interacts with and enhances binding of
various transcription factors including p53, SREBPs, and others.
supported_by:
- reference_id: PMID:19223331
supporting_text: Feb 17. HMGB1 and HMGB2 proteins up-regulate cellular
expression of human topoisomerase IIalpha.
- term:
id: GO:0005615
label: extracellular space
evidence_type: IDA
original_reference_id: PMID:25595774
review:
summary: HMGB1 is released to extracellular space as an alarmin.
action: ACCEPT
reason: Core localization for HMGB1's DAMP function. Well-documented
extracellular release.
supported_by:
- reference_id: PMID:25595774
supporting_text: '2015 Jan 16. Cutting Edge: identification of neutrophil
PGLYRP1 as a ligand for TREM-1.'
- term:
id: GO:0048018
label: receptor ligand activity
evidence_type: IDA
original_reference_id: PMID:17568691
review:
summary: HMGB1 acts as a ligand for TLR4, TLR2, RAGE receptors.
action: ACCEPT
reason: Core molecular function. HMGB1 is a bona fide receptor ligand for
multiple immune receptors (PMID:17568691).
supported_by:
- reference_id: PMID:17568691
supporting_text: 2007 May 25. Endogenous signals released from
necrotic cells augment inflammatory responses to bacterial
endotoxin.
- term:
id: GO:0006303
label: double-strand break repair via nonhomologous end joining
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: HMGB1 participates in NHEJ DNA repair.
action: ACCEPT
reason: Core nuclear function supported by sequence similarity.
- term:
id: GO:0010508
label: positive regulation of autophagy
evidence_type: IMP
original_reference_id: PMID:20819940
review:
summary: HMGB1 promotes autophagy through Beclin-1 interaction.
action: MARK_AS_OVER_ANNOTATED
reason: While HMGB1 can promote autophagy via Beclin-1 (PMID:20819940),
this is a secondary/pleiotropic function, not a core evolved function.
Core functions are chromatin biology and alarmin signaling.
supported_by:
- reference_id: PMID:20819940
supporting_text: Endogenous HMGB1 regulates autophagy.
- term:
id: GO:0003713
label: transcription coactivator activity
evidence_type: IDA
original_reference_id: PMID:19223331
review:
summary: HMGB1 has transcription coactivator activity enhancing
transcription factor binding.
action: ACCEPT
reason: Core nuclear function. HMGB1 enhances binding and activity of
various transcription factors (PMID:19223331).
supported_by:
- reference_id: PMID:19223331
supporting_text: Feb 17. HMGB1 and HMGB2 proteins up-regulate cellular
expression of human topoisomerase IIalpha.
- term:
id: GO:0005615
label: extracellular space
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: HMGB1 is released to extracellular space.
action: ACCEPT
reason: Core localization for alarmin function. Supported by sequence
similarity.
- term:
id: GO:0005634
label: nucleus
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: HMGB1 localizes to nucleus.
action: ACCEPT
reason: Core localization. Supported by sequence similarity to
characterized orthologs.
- term:
id: GO:0071222
label: cellular response to lipopolysaccharide
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: HMGB1 mediates cellular response to LPS.
action: ACCEPT
reason: HMGB1 binds LPS and enhances TLR4-mediated responses. Supported by
ISS.
- term:
id: GO:0000122
label: negative regulation of transcription by RNA polymerase II
evidence_type: IMP
original_reference_id: PMID:19158276
review:
summary: HMGB1 represses transcription in specific contexts.
action: ACCEPT
reason: Valid IMP evidence for transcription repression function.
supported_by:
- reference_id: PMID:19158276
supporting_text: Jan 21. Chromatin-specific remodeling by HMGB1 and
linker histone H1 silences proinflammatory genes during endotoxin
tolerance.
- term:
id: GO:0000122
label: negative regulation of transcription by RNA polymerase II
evidence_type: IGI
original_reference_id: PMID:19158276
review:
summary: HMGB1 involved in transcription repression.
action: ACCEPT
reason: Valid IGI evidence supporting transcription regulatory function.
supported_by:
- reference_id: PMID:19158276
supporting_text: Jan 21. Chromatin-specific remodeling by HMGB1 and
linker histone H1 silences proinflammatory genes during endotoxin
tolerance.
- term:
id: GO:0000976
label: transcription cis-regulatory region binding
evidence_type: IDA
original_reference_id: PMID:19158276
review:
summary: HMGB1 binds cis-regulatory regions of DNA.
action: ACCEPT
reason: Core function. HMGB1 binds DNA including regulatory regions to
modulate transcription.
supported_by:
- reference_id: PMID:19158276
supporting_text: Jan 21. Chromatin-specific remodeling by HMGB1 and
linker histone H1 silences proinflammatory genes during endotoxin
tolerance.
- term:
id: GO:0017053
label: transcription repressor complex
evidence_type: IDA
original_reference_id: PMID:19158276
review:
summary: HMGB1 is part of transcription repressor complexes.
action: ACCEPT
reason: Valid IDA evidence. HMGB1 can participate in transcription
repressor complexes.
supported_by:
- reference_id: PMID:19158276
supporting_text: Jan 21. Chromatin-specific remodeling by HMGB1 and
linker histone H1 silences proinflammatory genes during endotoxin
tolerance.
- term:
id: GO:0043536
label: positive regulation of blood vessel endothelial cell migration
evidence_type: IMP
original_reference_id: PMID:28276476
review:
summary: HMGB1 promotes endothelial cell migration as part of
proangiogenic activity.
action: KEEP_AS_NON_CORE
reason: Downstream pleiotropic effect of HMGB1's RAGE signaling.
supported_by:
- reference_id: PMID:28276476
supporting_text: miR-193a-3p interaction with HMGB1 downregulates
human endothelial cell proliferation and migration.
- term:
id: GO:1905564
label: positive regulation of vascular endothelial cell proliferation
evidence_type: IMP
original_reference_id: PMID:28276476
review:
summary: HMGB1 promotes vascular endothelial cell proliferation.
action: KEEP_AS_NON_CORE
reason: Downstream pleiotropic effect of HMGB1's proangiogenic signaling
through RAGE.
supported_by:
- reference_id: PMID:28276476
supporting_text: miR-193a-3p interaction with HMGB1 downregulates
human endothelial cell proliferation and migration.
- term:
id: GO:0005178
label: integrin binding
evidence_type: IDA
original_reference_id: PMID:20826760
review:
summary: HMGB1 binds alphav-beta3 integrin.
action: ACCEPT
reason: Valid IDA evidence. Integrin binding is part of HMGB1's
extracellular signaling repertoire.
supported_by:
- reference_id: PMID:20826760
supporting_text: HMGB1 inhibits macrophage activity in efferocytosis
through binding to the alphavbeta3-integrin.
- term:
id: GO:0035868
label: alphav-beta3 integrin-HMGB1 complex
evidence_type: IDA
original_reference_id: PMID:20826760
review:
summary: HMGB1 forms complex with alphav-beta3 integrin.
action: ACCEPT
reason: Valid IDA evidence for this specific protein complex
(PMID:20826760).
supported_by:
- reference_id: PMID:20826760
supporting_text: HMGB1 inhibits macrophage activity in efferocytosis
through binding to the alphavbeta3-integrin.
- term:
id: GO:2000426
label: negative regulation of apoptotic cell clearance
evidence_type: IDA
original_reference_id: PMID:20826760
review:
summary: HMGB1 inhibits phagocytosis of apoptotic cells.
action: ACCEPT
reason: HMGB1 binds phosphatidylserine on apoptotic cells and inhibits
their clearance (PMID:20826760).
supported_by:
- reference_id: PMID:20826760
supporting_text: HMGB1 inhibits macrophage activity in efferocytosis
through binding to the alphavbeta3-integrin.
- term:
id: GO:0034774
label: secretory granule lumen
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6798748
review:
summary: HMGB1 localizes to secretory granule lumen.
action: ACCEPT
reason: Valid TAS evidence. HMGB1 is secreted via secretory lysosomes.
- term:
id: GO:1904813
label: ficolin-1-rich granule lumen
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6800434
review:
summary: HMGB1 present in ficolin-1-rich granule lumen.
action: ACCEPT
reason: Valid Reactome TAS evidence for granule localization.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-166072
review:
summary: HMGB1 localizes to extracellular region in TLR signaling context.
action: ACCEPT
reason: Core localization. Reactome pathway annotation for HMGB1 in TLR
signaling.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-166082
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization for alarmin function. Reactome TAS evidence.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-166091
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-166119
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-166284
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-166286
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-166362
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-166363
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2201316
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2201322
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2262775
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2262777
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2559414
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5432825
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5602353
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5602383
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5602606
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6804099
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6804100
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6805981
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-937022
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-937059
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-937079
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0032755
label: positive regulation of interleukin-6 production
evidence_type: IDA
original_reference_id: PMID:26961863
review:
summary: HMGB1 induces IL-6 production.
action: ACCEPT
reason: Core alarmin function. Well-documented cytokine induction
(PMID:26961863).
supported_by:
- reference_id: PMID:26961863
supporting_text: Mar 9. AGEs and HMGB1 Increase Inflammatory Cytokine
Production from Human Placental Cells, Resulting in an Enhancement
of Monocyte Migration.
- term:
id: GO:0032757
label: positive regulation of interleukin-8 production
evidence_type: IDA
original_reference_id: PMID:26961863
review:
summary: HMGB1 induces IL-8/CXCL8 production.
action: ACCEPT
reason: Core alarmin function. Part of cytokine-inducing activity
(PMID:26961863).
supported_by:
- reference_id: PMID:26961863
supporting_text: Mar 9. AGEs and HMGB1 Increase Inflammatory Cytokine
Production from Human Placental Cells, Resulting in an Enhancement
of Monocyte Migration.
- term:
id: GO:2000343
label: positive regulation of chemokine (C-X-C motif) ligand 2 production
evidence_type: IDA
original_reference_id: PMID:26961863
review:
summary: HMGB1 induces CXCL2 production.
action: ACCEPT
reason: Core alarmin function. Part of chemokine-inducing activity.
supported_by:
- reference_id: PMID:26961863
supporting_text: Mar 9. AGEs and HMGB1 Increase Inflammatory Cytokine
Production from Human Placental Cells, Resulting in an Enhancement
of Monocyte Migration.
- term:
id: GO:0001786
label: phosphatidylserine binding
evidence_type: IDA
original_reference_id: PMID:18768881
review:
summary: HMGB1 binds phosphatidylserine on apoptotic cells.
action: ACCEPT
reason: Valid IDA evidence. HMGB1 binds PS and inhibits apoptotic cell
clearance (PMID:18768881).
supported_by:
- reference_id: PMID:18768881
supporting_text: High mobility group protein-1 inhibits phagocytosis
of apoptotic neutrophils through binding to phosphatidylserine.
- term:
id: GO:0002840
label: regulation of T cell mediated immune response to tumor cell
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: HMGB1 regulates T cell responses to tumors.
action: KEEP_AS_NON_CORE
reason: Pleiotropic immune effect. Supported by ISS.
- term:
id: GO:0032689
label: negative regulation of type II interferon production
evidence_type: IDA
original_reference_id: PMID:22473704
review:
summary: HMGB1 can suppress IFN-gamma production.
action: KEEP_AS_NON_CORE
reason: Context-dependent immunomodulatory effect (PMID:22473704).
supported_by:
- reference_id: PMID:22473704
supporting_text: HMGB1 conveys immunosuppressive characteristics on
regulatory and conventional T cells.
- term:
id: GO:0032733
label: positive regulation of interleukin-10 production
evidence_type: IDA
original_reference_id: PMID:22473704
review:
summary: HMGB1 induces IL-10 production.
action: KEEP_AS_NON_CORE
reason: Immunomodulatory effect. IL-10 induction is context-dependent
(PMID:22473704).
supported_by:
- reference_id: PMID:22473704
supporting_text: HMGB1 conveys immunosuppressive characteristics on
regulatory and conventional T cells.
- term:
id: GO:0032735
label: positive regulation of interleukin-12 production
evidence_type: IMP
original_reference_id: PMID:15944249
review:
summary: HMGB1 induces IL-12 production from dendritic cells.
action: ACCEPT
reason: Part of HMGB1's DC activation and Th1 polarization function
(PMID:15944249).
supported_by:
- reference_id: PMID:15944249
supporting_text: Release of high mobility group box 1 by dendritic
cells controls T cell activation via the receptor for advanced
glycation end products.
- term:
id: GO:0034165
label: positive regulation of toll-like receptor 9 signaling pathway
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: HMGB1 enhances TLR9 signaling.
action: ACCEPT
reason: Core alarmin function. HMGB1 facilitates TLR9 activation by
CpG-DNA.
- term:
id: GO:0035711
label: T-helper 1 cell activation
evidence_type: IDA
original_reference_id: PMID:22473704
review:
summary: HMGB1 activates Th1 cells.
action: KEEP_AS_NON_CORE
reason: Downstream effect of HMGB1's immune signaling. Context-dependent.
supported_by:
- reference_id: PMID:22473704
supporting_text: HMGB1 conveys immunosuppressive characteristics on
regulatory and conventional T cells.
- term:
id: GO:0042104
label: positive regulation of activated T cell proliferation
evidence_type: IMP
original_reference_id: PMID:15944249
review:
summary: HMGB1 promotes T cell proliferation.
action: KEEP_AS_NON_CORE
reason: Downstream pleiotropic effect of HMGB1's DC activation
(PMID:15944249).
supported_by:
- reference_id: PMID:15944249
supporting_text: Release of high mobility group box 1 by dendritic
cells controls T cell activation via the receptor for advanced
glycation end products.
- term:
id: GO:0043277
label: apoptotic cell clearance
evidence_type: IDA
original_reference_id: PMID:18768881
review:
summary: HMGB1 regulates apoptotic cell clearance by inhibiting
phagocytosis.
action: ACCEPT
reason: Valid IDA evidence. HMGB1 binds PS on apoptotic cells and inhibits
clearance (PMID:18768881).
supported_by:
- reference_id: PMID:18768881
supporting_text: High mobility group protein-1 inhibits phagocytosis
of apoptotic neutrophils through binding to phosphatidylserine.
- term:
id: GO:0043371
label: negative regulation of CD4-positive, alpha-beta T cell
differentiation
evidence_type: IDA
original_reference_id: PMID:22473704
review:
summary: HMGB1 negatively regulates CD4 T cell differentiation.
action: KEEP_AS_NON_CORE
reason: Context-dependent immunomodulatory effect (PMID:22473704).
supported_by:
- reference_id: PMID:22473704
supporting_text: HMGB1 conveys immunosuppressive characteristics on
regulatory and conventional T cells.
- term:
id: GO:0045063
label: T-helper 1 cell differentiation
evidence_type: IMP
original_reference_id: PMID:15944249
review:
summary: HMGB1 promotes Th1 differentiation.
action: KEEP_AS_NON_CORE
reason: Downstream effect of DC activation (PMID:15944249).
supported_by:
- reference_id: PMID:15944249
supporting_text: Release of high mobility group box 1 by dendritic
cells controls T cell activation via the receptor for advanced
glycation end products.
- term:
id: GO:0097350
label: neutrophil clearance
evidence_type: IDA
original_reference_id: PMID:18768881
review:
summary: HMGB1 regulates neutrophil clearance.
action: ACCEPT
reason: Valid IDA evidence related to apoptotic cell clearance
(PMID:18768881).
supported_by:
- reference_id: PMID:18768881
supporting_text: High mobility group protein-1 inhibits phagocytosis
of apoptotic neutrophils through binding to phosphatidylserine.
- term:
id: GO:2001200
label: positive regulation of dendritic cell differentiation
evidence_type: IMP
original_reference_id: PMID:15944249
review:
summary: HMGB1 promotes dendritic cell differentiation.
action: KEEP_AS_NON_CORE
reason: Downstream pleiotropic effect of alarmin signaling
(PMID:15944249).
supported_by:
- reference_id: PMID:15944249
supporting_text: Release of high mobility group box 1 by dendritic
cells controls T cell activation via the receptor for advanced
glycation end products.
- term:
id: GO:0002643
label: regulation of tolerance induction
evidence_type: IDA
original_reference_id: PMID:18631454
review:
summary: Oxidized HMGB1 from apoptotic cells promotes immune tolerance.
action: ACCEPT
reason: Valid IDA evidence. Sulfonyl HMGB1 promotes tolerance through
Cys-106 oxidation (PMID:18631454).
supported_by:
- reference_id: PMID:18631454
supporting_text: Induction of immunological tolerance by apoptotic
cells requires caspase-dependent oxidation of high-mobility group
box-1 protein.
- term:
id: GO:0007204
label: positive regulation of cytosolic calcium ion concentration
evidence_type: IDA
original_reference_id: PMID:22370717
review:
summary: HMGB1-CXCL12 complex induces calcium signaling via CXCR4.
action: ACCEPT
reason: Valid IDA evidence. CXCR4 signaling involves calcium mobilization
(PMID:22370717).
supported_by:
- reference_id: PMID:22370717
supporting_text: HMGB1 promotes recruitment of inflammatory cells to
damaged tissues by forming a complex with CXCL12 and signaling via
CXCR4.
- term:
id: GO:0019958
label: C-X-C chemokine binding
evidence_type: IDA
original_reference_id: PMID:22370717
review:
summary: HMGB1 binds CXCL12 to form a heterocomplex.
action: ACCEPT
reason: Core function. HMGB1-CXCL12 binding is essential for
CXCR4-mediated chemotaxis (PMID:22370717).
supported_by:
- reference_id: PMID:22370717
supporting_text: HMGB1 promotes recruitment of inflammatory cells to
damaged tissues by forming a complex with CXCL12 and signaling via
CXCR4.
- term:
id: GO:0070374
label: positive regulation of ERK1 and ERK2 cascade
evidence_type: IDA
original_reference_id: PMID:22370717
review:
summary: HMGB1-CXCL12 activates ERK1/2 via CXCR4.
action: ACCEPT
reason: Valid IDA evidence. ERK activation is part of CXCR4 signaling
(PMID:22370717).
supported_by:
- reference_id: PMID:22370717
supporting_text: HMGB1 promotes recruitment of inflammatory cells to
damaged tissues by forming a complex with CXCL12 and signaling via
CXCR4.
- term:
id: GO:0090026
label: positive regulation of monocyte chemotaxis
evidence_type: IDA
original_reference_id: PMID:22370717
review:
summary: HMGB1-CXCL12 promotes monocyte chemotaxis.
action: ACCEPT
reason: Core extracellular function. Well-documented in PMID:22370717.
supported_by:
- reference_id: PMID:22370717
supporting_text: HMGB1 promotes recruitment of inflammatory cells to
damaged tissues by forming a complex with CXCL12 and signaling via
CXCR4.
- term:
id: GO:0003684
label: damaged DNA binding
evidence_type: IDA
original_reference_id: PMID:17803946
review:
summary: HMGB1 binds damaged DNA in base excision repair.
action: ACCEPT
reason: Core nuclear function. HMGB1 binds damaged DNA as part of BER
(PMID:17803946).
supported_by:
- reference_id: PMID:17803946
supporting_text: HMGB1 is a cofactor in mammalian base excision
repair.
- term:
id: GO:0016829
label: lyase activity
evidence_type: IDA
original_reference_id: PMID:17803946
review:
summary: HMGB1 has lyase activity in BER context.
action: UNDECIDED
reason: This annotation requires careful review. HMGB1 stimulates AP lyase
activity but may not itself be the lyase.
supported_by:
- reference_id: PMID:17803946
supporting_text: HMGB1 is a cofactor in mammalian base excision
repair.
- term:
id: GO:0032425
label: positive regulation of mismatch repair
evidence_type: IDA
original_reference_id: PMID:15014079
review:
summary: HMGB1 positively regulates mismatch repair.
action: ACCEPT
reason: Core nuclear function. HMGB1 is involved in MMR through MSH2
interaction (PMID:15014079).
supported_by:
- reference_id: PMID:15014079
supporting_text: 2004 Mar 9. Evidence for involvement of HMGB1 protein
in human DNA mismatch repair.
- term:
id: GO:0070182
label: DNA polymerase binding
evidence_type: IDA
original_reference_id: PMID:17803946
review:
summary: HMGB1 binds DNA polymerase beta in BER.
action: ACCEPT
reason: Valid IDA evidence. HMGB1 interacts with POLB in BER
(PMID:17803946).
supported_by:
- reference_id: PMID:17803946
supporting_text: HMGB1 is a cofactor in mammalian base excision
repair.
- term:
id: GO:0002218
label: activation of innate immune response
evidence_type: IDA
original_reference_id: PMID:24971542
review:
summary: HMGB1 activates innate immune response via AIM2 inflammasome.
action: ACCEPT
reason: Core alarmin function. HMGB1 promotes AIM2 inflammasome activation
(PMID:24971542).
supported_by:
- reference_id: PMID:24971542
supporting_text: HMGB1-DNA complex-induced autophagy limits AIM2
inflammasome activation through RAGE.
- term:
id: GO:0032732
label: positive regulation of interleukin-1 production
evidence_type: IDA
original_reference_id: PMID:12765338
review:
summary: HMGB1 induces IL-1 production.
action: ACCEPT
reason: Core alarmin function. Well-documented cytokine induction
(PMID:12765338).
supported_by:
- reference_id: PMID:12765338
supporting_text: Structural basis for the proinflammatory cytokine
activity of high mobility group box 1.
- term:
id: GO:0032755
label: positive regulation of interleukin-6 production
evidence_type: IDA
original_reference_id: PMID:12765338
review:
summary: HMGB1 induces IL-6 production.
action: ACCEPT
reason: Core alarmin function. Well-documented (PMID:12765338).
supported_by:
- reference_id: PMID:12765338
supporting_text: Structural basis for the proinflammatory cytokine
activity of high mobility group box 1.
- term:
id: GO:0032760
label: positive regulation of tumor necrosis factor production
evidence_type: IDA
original_reference_id: PMID:12765338
review:
summary: HMGB1 induces TNF production.
action: ACCEPT
reason: Core alarmin function. Well-documented (PMID:12765338).
supported_by:
- reference_id: PMID:12765338
supporting_text: Structural basis for the proinflammatory cytokine
activity of high mobility group box 1.
- term:
id: GO:0043410
label: positive regulation of MAPK cascade
evidence_type: IDA
original_reference_id: PMID:12765338
review:
summary: HMGB1 activates MAPK signaling.
action: ACCEPT
reason: Valid IDA evidence. MAPK activation through receptor signaling
(PMID:12765338).
supported_by:
- reference_id: PMID:12765338
supporting_text: Structural basis for the proinflammatory cytokine
activity of high mobility group box 1.
- term:
id: GO:0046330
label: positive regulation of JNK cascade
evidence_type: IDA
original_reference_id: PMID:12765338
review:
summary: HMGB1 activates JNK signaling.
action: ACCEPT
reason: Valid IDA evidence. JNK activation through receptor signaling
(PMID:12765338).
supported_by:
- reference_id: PMID:12765338
supporting_text: Structural basis for the proinflammatory cytokine
activity of high mobility group box 1.
- term:
id: GO:0001530
label: lipopolysaccharide binding
evidence_type: IDA
original_reference_id: PMID:21660935
review:
summary: HMGB1 binds LPS and transfers it to CD14.
action: ACCEPT
reason: Core function. HMGB1 binds LPS and enhances TLR4 signaling
(PMID:21660935).
supported_by:
- reference_id: PMID:21660935
supporting_text: Aug 4. Identification of lipopolysaccharide-binding
peptide regions within HMGB1 and their effects on subclinical
endotoxemia in a mouse model.
- term:
id: GO:0000400
label: four-way junction DNA binding
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: HMGB1 binds four-way junction DNA structures.
action: ACCEPT
reason: Core function. HMGB1 preferentially binds non-canonical DNA
structures including cruciform DNA.
- term:
id: GO:0000405
label: bubble DNA binding
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: HMGB1 binds bubble DNA structures.
action: ACCEPT
reason: Core function. HMGB1 binds distorted DNA structures.
- term:
id: GO:0008301
label: DNA binding, bending
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: HMGB1 binds and bends DNA.
action: ACCEPT
reason: Core molecular function. DNA bending is fundamental to HMGB1's
chromatin function.
- term:
id: GO:0032392
label: DNA geometric change
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: HMGB1 induces DNA geometric changes.
action: ACCEPT
reason: Core function. HMGB1 bends DNA and alters its geometry.
- term:
id: GO:0097100
label: supercoiled DNA binding
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: HMGB1 binds supercoiled DNA.
action: ACCEPT
reason: Core function. HMGB1 preferentially binds non-canonical DNA
including supercoiled DNA.
- term:
id: GO:0003723
label: RNA binding
evidence_type: HDA
original_reference_id: PMID:22658674
review:
summary: HMGB1 binds RNA as a nucleic acid biosensor.
action: ACCEPT
reason: HMGB1 binds various nucleic acids including RNA. HDA evidence from
interactome capture.
supported_by:
- reference_id: PMID:22658674
supporting_text: May 31. Insights into RNA biology from an atlas of
mammalian mRNA-binding proteins.
- term:
id: GO:0003723
label: RNA binding
evidence_type: HDA
original_reference_id: PMID:22681889
review:
summary: HMGB1 binds RNA.
action: ACCEPT
reason: Valid HDA evidence from interactome studies (PMID:22681889).
supported_by:
- reference_id: PMID:22681889
supporting_text: The mRNA-bound proteome and its global occupancy
profile on protein-coding transcripts.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6798748
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6800434
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-879411
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-NUL-997411
review:
summary: HMGB1 in extracellular region.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-266204
review:
summary: HMGB1 in nucleoplasm.
action: ACCEPT
reason: Core localization. Reactome TAS evidence for V(D)J recombination.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6805981
review:
summary: HMGB1 in nucleoplasm.
action: ACCEPT
reason: Core localization. Reactome TAS evidence.
- term:
id: GO:0006954
label: inflammatory response
evidence_type: IDA
original_reference_id: PMID:23146691
review:
summary: HMGB1 promotes inflammatory response.
action: ACCEPT
reason: Core alarmin function. Well-documented (PMID:23146691).
supported_by:
- reference_id: PMID:23146691
supporting_text: 2012 Nov 9. Emodin-6-O-β-D-glucoside inhibits
HMGB1-induced inflammatory responses in vitro and in vivo.
- term:
id: GO:0043537
label: negative regulation of blood vessel endothelial cell migration
evidence_type: IDA
original_reference_id: PMID:23148224
review:
summary: HMGB1 can inhibit endothelial migration via TLR4.
action: KEEP_AS_NON_CORE
reason: Context-dependent pleiotropic effect (PMID:23148224).
supported_by:
- reference_id: PMID:23148224
supporting_text: 2012 Nov 12. High mobility group Box 1 inhibits human
pulmonary artery endothelial cell migration via a Toll-like receptor
4- and interferon response factor 3-dependent mechanism(s).
- term:
id: GO:0005615
label: extracellular space
evidence_type: IDA
original_reference_id: PMID:19841752
review:
summary: HMGB1 in extracellular space.
action: ACCEPT
reason: Core localization. IDA evidence.
supported_by:
- reference_id: PMID:19841752
supporting_text: 'Linking innate and adaptive immunity: human Vgamma9Vdelta2
T cells enhance CD40 expression and HMGB-1 secretion.'
- term:
id: GO:0009986
label: cell surface
evidence_type: IDA
original_reference_id: PMID:19841752
review:
summary: HMGB1 on cell surface.
action: ACCEPT
reason: Valid IDA evidence. HMGB1 on surface of activated cells
(PMID:19841752).
supported_by:
- reference_id: PMID:19841752
supporting_text: 'Linking innate and adaptive immunity: human Vgamma9Vdelta2
T cells enhance CD40 expression and HMGB-1 secretion.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19505873
review:
summary: HMGB1 binds proteins.
action: ACCEPT
reason: Valid IPI evidence from interactome study.
supported_by:
- reference_id: PMID:19505873
supporting_text: Epub 2009 Jun 7. Complementary quantitative
proteomics reveals that transcription factor AP-4 mediates
E-box-dependent complex formation for transcriptional repression of
HDM2.
- term:
id: GO:0031175
label: neuron projection development
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: HMGB1 involved in neuron projection development via RAGE.
action: KEEP_AS_NON_CORE
reason: Tissue-specific pleiotropic effect through RAGE signaling.
- term:
id: GO:0043388
label: positive regulation of DNA binding
evidence_type: IDA
original_reference_id: PMID:11748232
review:
summary: HMGB1 enhances DNA binding of transcription factors.
action: ACCEPT
reason: Core function. HMGB1 enhances DNA binding of p53 and other
transcription factors (PMID:11748232).
supported_by:
- reference_id: PMID:11748232
supporting_text: Dec 17. HMGB1 and HMGB2 cell-specifically
down-regulate the p53- and p73-dependent sequence-specific
transactivation from the human Bax gene promoter.
- term:
id: GO:0050786
label: RAGE receptor binding
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: HMGB1 binds RAGE receptor.
action: ACCEPT
reason: Core alarmin function. RAGE binding is essential for many HMGB1
extracellular effects.
- term:
id: GO:0001773
label: myeloid dendritic cell activation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: HMGB1 activates dendritic cells.
action: KEEP_AS_NON_CORE
reason: Downstream effect of alarmin signaling. ISS evidence.
- term:
id: GO:0002407
label: dendritic cell chemotaxis
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: HMGB1 promotes dendritic cell chemotaxis.
action: KEEP_AS_NON_CORE
reason: Downstream pleiotropic effect. ISS evidence.
- term:
id: GO:0002437
label: inflammatory response to antigenic stimulus
evidence_type: IEP
original_reference_id: PMID:19841752
review:
summary: HMGB1 elevated during inflammatory response to antigen.
action: ACCEPT
reason: Valid IEP evidence. HMGB1 elevated in inflammatory contexts.
supported_by:
- reference_id: PMID:19841752
supporting_text: 'Linking innate and adaptive immunity: human Vgamma9Vdelta2
T cells enhance CD40 expression and HMGB-1 secretion.'
- term:
id: GO:0003684
label: damaged DNA binding
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: HMGB1 binds damaged DNA.
action: ACCEPT
reason: Core function. ISS evidence supporting damaged DNA binding.
- term:
id: GO:0005125
label: cytokine activity
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: HMGB1 has cytokine activity.
action: ACCEPT
reason: Core extracellular function. Disulfide HMGB1 has cytokine-like
activity. ISS evidence.
- term:
id: GO:0033151
label: V(D)J recombination
evidence_type: IDA
original_reference_id: PMID:9166431
review:
summary: HMGB1 is a cofactor in V(D)J recombination.
action: ACCEPT
reason: Core nuclear function. HMGB1 stimulates RAG cleavage in V(D)J
recombination (PMID:9166431).
supported_by:
- reference_id: PMID:9166431
supporting_text: 'V(D)J recombination: modulation of RAG1 and RAG2 cleavage
activity on 12/23 substrates by whole cell extract and DNA-bending proteins.'
- term:
id: GO:0042056
label: chemoattractant activity
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: HMGB1 has chemoattractant activity.
action: ACCEPT
reason: Core extracellular function. All-thiol HMGB1 with CXCL12 is
chemotactic. ISS evidence.
- term:
id: GO:0043065
label: positive regulation of apoptotic process
evidence_type: IDA
original_reference_id: PMID:19800306
review:
summary: HMGB1 can promote apoptosis in certain contexts.
action: KEEP_AS_NON_CORE
reason: Context-dependent effect (PMID:19800306). Not a core function.
supported_by:
- reference_id: PMID:19800306
supporting_text: Epub 2009 Oct 1. Effect of high mobility group box-1
protein on apoptosis of peritoneal macrophages.
- term:
id: GO:0003690
label: double-stranded DNA binding
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: HMGB1 binds double-stranded DNA through its HMG-box domains A and
B. This is a well-established core function.
action: ACCEPT
reason: DNA binding is a fundamental function of HMGB1. The protein binds
dsDNA through its HMG-box domains (PMID:8339930). ISS transfer from
ortholog is appropriate.
supported_by:
- reference_id: PMID:8339930
supporting_text: "The mammalian high mobility group proteins HMG1 and HMG2
are abundant, chromatin-associated proteins"
- term:
id: GO:0003697
label: single-stranded DNA binding
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: HMGB1 has been shown to bind single-stranded DNA in addition to
dsDNA through its HMG-box domains.
action: ACCEPT
reason: HMGB1 binds various DNA structures including ssDNA. ISS transfer
from ortholog data is appropriate given the conserved DNA-binding
HMG-box domains.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:11748232
review:
summary: This study demonstrates HMGB1 physically interacts with p53 and
p73 transcription factors, enhancing their DNA binding. The generic
protein binding term should be replaced with a more specific term.
action: MODIFY
reason: HMGB1 interacts with p53 and p73 transcription factors to modulate
their DNA binding activity (PMID:11748232). The generic protein binding
term is uninformative; a more specific term for transcription factor
binding is appropriate.
proposed_replacement_terms:
- id: GO:0140297
label: DNA-binding transcription factor binding
supported_by:
- reference_id: PMID:11748232
supporting_text: "HMGB1 physically interacts with two splicing variants
of p73, alpha and beta (pull-down assay), and enhances binding of p73
to specific cognate DNA sites"
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:19223331
review:
summary: HMGB1 is a chromatin-associated nuclear protein that shuttles
between nucleus and cytoplasm. Nuclear localization is well-established.
action: ACCEPT
reason: Nuclear localization is a core characteristic of HMGB1 as a
chromatin-associated protein (PMID:19223331). The protein is
predominantly nuclear in basal state.
supported_by:
- reference_id: PMID:19223331
supporting_text: "HMGB1 is associated with chromosomes in mitosis and due
to its extreme mobility in the cell the protein is continuously exchanged
between nucleus and cytoplasm"
- term:
id: GO:0006265
label: DNA topological change
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: HMGB1 binding causes DNA bending and topological changes. The
protein can promote DNA circularization and alter DNA topology.
action: ACCEPT
reason: HMGB1 induces DNA topological changes through its DNA-bending
activity (PMID:8339930). This is a core biochemical function
demonstrated by circularization assays.
supported_by:
- reference_id: PMID:8339930
supporting_text: "HMG1 and HMG2 can bend DNA extremely efficiently, forming
circles as small as 66 bp"
- term:
id: GO:0006310
label: DNA recombination
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: HMGB1 participates in DNA recombination including V(D)J
recombination by facilitating DNA bending and promoting assembly of
nucleoprotein complexes.
action: ACCEPT
reason: HMGB1 promotes DNA recombination by facilitating DNA flexibility
and nucleoprotein complex assembly (PMID:8339930). This is a core
nuclear function.
supported_by:
- reference_id: PMID:8339930
supporting_text: "these proteins can substitute for the prokaryotic DNA-bending
protein HU in promoting the assembly of the Hin invertasome, an intermediate
structure in Hin-mediated site-specific DNA inversion"
- term:
id: GO:0008301
label: DNA binding, bending
evidence_type: IMP
original_reference_id: PMID:19223331
review:
summary: HMGB1 DNA bending is a core function. The study showed that
HMGB1, but not a mutant incapable of DNA bending, activates the topo
IIalpha promoter.
action: ACCEPT
reason: DNA bending is a fundamental function of HMGB1 demonstrated by IMP
evidence. The study shows DNA bending is required for HMGB1 to activate
topo IIalpha promoter (PMID:19223331).
supported_by:
- reference_id: PMID:19223331
supporting_text: "HMGB1, but not a mutant of HMGB1 incapable of DNA bending,
up-regulates the activity of the topo IIalpha promoter in human cells"
- term:
id: GO:0043388
label: positive regulation of DNA binding
evidence_type: IDA
original_reference_id: PMID:19223331
review:
summary: HMGB1 enhances DNA binding of transcription factors like NF-Y and
p53/p73 family members by modulating DNA structure.
action: ACCEPT
reason: HMGB1 positively regulates DNA binding by modulating transcription
factor NF-Y binding to promoters (PMID:19223331). This is a core
function related to its transcriptional coregulator role.
supported_by:
- reference_id: PMID:19223331
supporting_text: "Our experiments suggest a mechanism of up-regulation of
cellular expression of topo IIalpha by HMGB1/2 in pRb-negative cells by
modulation of binding of transcription factor NF-Y to the topo IIalpha
promoter"
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:19223331
review:
summary: HMGB1 upregulates topo IIalpha promoter activity through
luciferase reporter assays in pRb-negative cells.
action: ACCEPT
reason: HMGB1 positively regulates transcription by RNA pol II as
demonstrated by luciferase reporter assays showing upregulation of topo
IIalpha promoter (PMID:19223331). This is a core transcriptional
coregulator function.
supported_by:
- reference_id: PMID:19223331
supporting_text: "Using luciferase gene reporter assay we have demonstrated
that HMGB1, but not a mutant of HMGB1 incapable of DNA bending, up-regulated
the activity of human topo IIalpha promoter in human cells that lack functional
retinoblastoma protein pRb"
- term:
id: GO:0140297
label: DNA-binding transcription factor binding
evidence_type: IPI
original_reference_id: PMID:19223331
review:
summary: HMGB1 interacts with transcription factors including NF-Y to
modulate their DNA binding activity and transcriptional output.
action: ACCEPT
reason: HMGB1 interacts with and modulates the activity of DNA-binding
transcription factors like NF-Y (PMID:19223331) and p53/p73 family
members. This is a specific and accurate molecular function term.
supported_by:
- reference_id: PMID:19223331
supporting_text: "HMGB1 also interacts weakly with a number of proteins,
including transcriptional factors, site-specific recombination and DNA
repair proteins"
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:8339930
review:
summary: HMGB1 is an abundant chromatin-associated nuclear protein.
Nuclear localization is fundamental to its function.
action: ACCEPT
reason: Nuclear localization is a core characteristic of HMGB1 as an
abundant chromatin-associated protein (PMID:8339930). This is
well-established and fundamental to its biological role.
supported_by:
- reference_id: PMID:8339930
supporting_text: "The mammalian high mobility group proteins HMG1 and HMG2
are abundant, chromatin-associated proteins"
- term:
id: GO:0000793
label: condensed chromosome
evidence_type: IDA
original_reference_id: PMID:12925773
review:
summary: HMGB1 associates with condensed chromosomes during mitosis. Live
cell imaging shows the protein exchanges rapidly between free and
chromosome-bound forms.
action: ACCEPT
reason: HMGB1 associates with condensed chromatin during mitosis as shown
by fluorescent protein tagging in live cells (PMID:12925773). This is a
core function related to its chromatin-binding role.
supported_by:
- reference_id: PMID:12925773
supporting_text: "HMGB1 and 2 were shown to be present under two forms in
mitotic cells, i.e., free and associated with the condensed chromatin,
which rapidly exchange"
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:8006019
review:
summary: This study demonstrates HMGB1 physically interacts with TBP
(TATA-binding protein) to inhibit preinitiation complex assembly. The
generic term should be replaced with a more specific binding term.
action: MODIFY
reason: HMGB1 interacts with TBP to form an HMG1.TBP.promoter complex that
blocks TFIIB binding (PMID:8006019). The generic protein binding term is
uninformative; a more specific term for transcription machinery
component binding is appropriate.
proposed_replacement_terms:
- id: GO:0140297
label: DNA-binding transcription factor binding
supported_by:
- reference_id: PMID:8006019
supporting_text: "purified mammalian HMG1, as well as recombinant human
HMG1, can interact with TATA-binding protein (TBP) in the presence of
a TATA box-containing oligonucleotide to form a specific HMG1.TBP.promoter
complex"
- term:
id: GO:0017055
label: negative regulation of RNA polymerase II transcription
preinitiation complex assembly
evidence_type: IDA
original_reference_id: PMID:8006019
review:
summary: HMGB1 interacts with TBP to form a complex that prevents TFIIB
binding and blocks preinitiation complex formation. In vitro, HMGB1
inhibits transcription by RNA pol II over 30-fold.
action: ACCEPT
reason: HMGB1 inhibits preinitiation complex assembly by binding TBP and
blocking TFIIB recruitment (PMID:8006019). This is a well-characterized
transcriptional regulatory function with direct assay evidence.
supported_by:
- reference_id: PMID:8006019
supporting_text: "This complex prevents TFIIB binding to TBP and consequently
blocks formation of the preinitiation complex"
core_functions:
- molecular_function:
id: GO:0008301
label: DNA binding, bending
description: >-
HMGB1 binds and bends DNA through its two HMG-box domains (A and B). DNA bending
is
essential for its function as demonstrated by mutant studies showing that HMGB1
incapable
of DNA bending fails to activate target promoters (PMID:19223331). The protein
can bend
DNA to form circles as small as 66 bp (PMID:8339930).
directly_involved_in:
- id: GO:0006265
label: DNA topological change
locations:
- id: GO:0005634
label: nucleus
- molecular_function:
id: GO:0140297
label: DNA-binding transcription factor binding
description: >-
HMGB1 acts as a transcriptional coregulator by binding transcription factors
(p53, p73,
NF-Y, TBP) and modulating their DNA binding activity. It can both positively
and negatively
regulate transcription depending on cellular context (PMID:8006019, PMID:19223331,
PMID:11748232).
directly_involved_in:
- id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
locations:
- id: GO:0005634
label: nucleus
- molecular_function:
id: GO:0005125
label: cytokine activity
description: >-
Extracellular HMGB1 acts as a DAMP/alarmin released from necrotic or activated
cells,
signaling through TLR4, TLR2, RAGE, and CXCR4 (via CXCL12 heterocomplex) to
promote
inflammation and chemotaxis. The all-thiol redox form is chemotactic, the disulfide
form
induces cytokine production, and the fully oxidized form is inactive.
directly_involved_in:
- id: GO:0006954
label: inflammatory response
locations:
- id: GO:0005576
label: extracellular region
references:
- id: GO_REF:0000024
title: Manual transfer of experimentally-verified manual GO annotation data
to orthologs by curator judgment of sequence similarity
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000043
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword
mapping
findings: []
- id: GO_REF:0000044
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular
Location vocabulary mapping, accompanied by conservative changes to GO
terms applied by UniProt
findings: []
- id: GO_REF:0000052
title: Gene Ontology annotation based on curation of immunofluorescence data
findings: []
- id: GO_REF:0000107
title: Automatic transfer of experimentally verified manual GO annotation
data to orthologs using Ensembl Compara
findings: []
- id: GO_REF:0000108
title: Automatic assignment of GO terms using logical inference, based on on
inter-ontology links
findings: []
- id: GO_REF:0000117
title: Electronic Gene Ontology annotations created by ARBA machine learning
models
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:11748232
title: HMGB1 and HMGB2 cell-specifically down-regulate the p53- and
p73-dependent sequence-specific transactivation from the human Bax gene
promoter.
findings: []
- id: PMID:12765338
title: Structural basis for the proinflammatory cytokine activity of high
mobility group box 1.
findings: []
- id: PMID:12925773
title: Association of chromatin proteins high mobility group box (HMGB) 1
and HMGB2 with mitotic chromosomes.
findings: []
- id: PMID:15014079
title: Evidence for involvement of HMGB1 protein in human DNA mismatch
repair.
findings: []
- id: PMID:15379539
title: The long acidic tail of high mobility group box 1 (HMGB1) protein
forms an extended and flexible structure that interacts with specific
residues within and between the HMG boxes.
findings: []
- id: PMID:15944249
title: Release of high mobility group box 1 by dendritic cells controls T
cell activation via the receptor for advanced glycation end products.
findings: []
- id: PMID:17568691
title: Endogenous signals released from necrotic cells augment inflammatory
responses to bacterial endotoxin.
findings: []
- id: PMID:17803946
title: HMGB1 is a cofactor in mammalian base excision repair.
findings: []
- id: PMID:18631454
title: Induction of immunological tolerance by apoptotic cells requires
caspase-dependent oxidation of high-mobility group box-1 protein.
findings: []
- id: PMID:18768881
title: High mobility group protein-1 inhibits phagocytosis of apoptotic
neutrophils through binding to phosphatidylserine.
findings: []
- id: PMID:19158276
title: Chromatin-specific remodeling by HMGB1 and linker histone H1 silences
proinflammatory genes during endotoxin tolerance.
findings: []
- id: PMID:19223331
title: HMGB1 and HMGB2 proteins up-regulate cellular expression of human
topoisomerase IIalpha.
findings: []
- id: PMID:19505873
title: Complementary quantitative proteomics reveals that transcription
factor AP-4 mediates E-box-dependent complex formation for transcriptional
repression of HDM2.
findings: []
- id: PMID:19800306
title: Effect of high mobility group box-1 protein on apoptosis of
peritoneal macrophages.
findings: []
- id: PMID:19841752
title: 'Linking innate and adaptive immunity: human Vgamma9Vdelta2 T cells enhance
CD40 expression and HMGB-1 secretion.'
findings: []
- id: PMID:20819940
title: Endogenous HMGB1 regulates autophagy.
findings: []
- id: PMID:20826760
title: HMGB1 inhibits macrophage activity in efferocytosis through binding
to the alphavbeta3-integrin.
findings: []
- id: PMID:21660935
title: Identification of lipopolysaccharide-binding peptide regions within
HMGB1 and their effects on subclinical endotoxemia in a mouse model.
findings: []
- id: PMID:22370717
title: HMGB1 promotes recruitment of inflammatory cells to damaged tissues
by forming a complex with CXCL12 and signaling via CXCR4.
findings: []
- id: PMID:22473704
title: HMGB1 conveys immunosuppressive characteristics on regulatory and
conventional T cells.
findings: []
- id: PMID:22658674
title: Insights into RNA biology from an atlas of mammalian mRNA-binding
proteins.
findings: []
- id: PMID:22681889
title: The mRNA-bound proteome and its global occupancy profile on
protein-coding transcripts.
findings: []
- id: PMID:23063560
title: HMGB1-facilitated p53 DNA binding occurs via HMG-Box/p53
transactivation domain interaction, regulated by the acidic tail.
findings: []
- id: PMID:23146691
title: Emodin-6-O-β-D-glucoside inhibits HMGB1-induced inflammatory
responses in vitro and in vivo.
findings: []
- id: PMID:23148224
title: High mobility group Box 1 inhibits human pulmonary artery endothelial
cell migration via a Toll-like receptor 4- and interferon response factor
3-dependent mechanism(s).
findings: []
- id: PMID:23303669
title: Chaperone-like activity of high-mobility group box 1 protein and its
role in reducing the formation of polyglutamine aggregates.
findings: []
- id: PMID:24474694
title: An immunogenic peptide in the A-box of HMGB1 protein reverses
apoptosis-induced tolerance through RAGE receptor.
findings: []
- id: PMID:24971542
title: HMGB1-DNA complex-induced autophagy limits AIM2 inflammasome
activation through RAGE.
findings: []
- id: PMID:25416956
title: A proteome-scale map of the human interactome network.
findings: []
- id: PMID:25595774
title: 'Cutting Edge: identification of neutrophil PGLYRP1 as a ligand for TREM-1.'
findings: []
- id: PMID:26961863
title: AGEs and HMGB1 Increase Inflammatory Cytokine Production from Human
Placental Cells, Resulting in an Enhancement of Monocyte Migration.
findings: []
- id: PMID:28276476
title: miR-193a-3p interaction with HMGB1 downregulates human endothelial
cell proliferation and migration.
findings: []
- id: PMID:28514442
title: Architecture of the human interactome defines protein communities and
disease networks.
findings: []
- id: PMID:29721183
title: Delineating the HMGB1 and HMGB2 interactome in prostate and ovary
epithelial cells and its relationship with cancer.
findings: []
- id: PMID:31694235
title: 'Characterization of HMGB1/2 Interactome in Prostate Cancer by Yeast Two
Hybrid Approach: Potential Pathobiological Implications.'
findings: []
- id: PMID:32296183
title: A reference map of the human binary protein interactome.
findings: []
- id: PMID:32814053
title: Interactome Mapping Provides a Network of Neurodegenerative Disease
Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
findings: []
- id: PMID:32867128
title: The HMGB1-2 Ovarian Cancer Interactome. The Role of HMGB Proteins and
Their Interacting Partners MIEN1 and NOP53 in Ovary Cancer and
Drug-Response.
findings: []
- id: PMID:33147444
title: Genome-wide CRISPR Screens Reveal Host Factors Critical for
SARS-CoV-2 Infection.
findings: []
- id: PMID:33961781
title: Dual proteome-scale networks reveal cell-specific remodeling of the
human interactome.
findings: []
- id: PMID:35239449
title: SARS-CoV-2 ORF3a induces RETREG1/FAM134B-dependent reticulophagy and
triggers sequential ER stress and inflammatory responses during SARS-CoV-2
infection.
findings: []
- id: PMID:40205054
title: Multimodal cell maps as a foundation for structural and functional
genomics.
findings: []
- id: PMID:8006019
title: The high mobility group protein HMG1 can reversibly inhibit class II
gene transcription by interaction with the TATA-binding protein.
findings: []
- id: PMID:8339930
title: The nonspecific DNA-binding and -bending proteins HMG1 and HMG2
promote the assembly of complex nucleoprotein structures.
findings: []
- id: PMID:9166431
title: 'V(D)J recombination: modulation of RAG1 and RAG2 cleavage activity on
12/23 substrates by whole cell extract and DNA-bending proteins.'
findings: []
- id: PMID:9472015
title: High mobility group protein-1 (HMG-1) is a unique activator of p53.
findings: []
- id: Reactome:R-HSA-166072
title: MyD88 forms a complex with TIRAP:activated TLR2/4
findings: []
- id: Reactome:R-HSA-166082
title: IRAK4 binds to the activated TLR receptor:TIRAP:MyD88 complex
findings: []
- id: Reactome:R-HSA-166091
title: IRAK1 or IRAK2 binds to the activated IRAK4 :activated
TLR:MyD88:TIRAP complex
findings: []
- id: Reactome:R-HSA-166119
title: First phosphorylation of IRAK1 by IRAK4 bound to activated
TLR:MyD88:Mal
findings: []
- id: Reactome:R-HSA-166284
title: Second phosphorylation of IRAK1 by IRAK4 bound to activated
TLR:MyD88:TIRAP
findings: []
- id: Reactome:R-HSA-166286
title: Multiple IRAK1 autophosphorylation steps
findings: []
- id: Reactome:R-HSA-166362
title: Dissociation of hp-IRAK1:TRAF6 from the activated
TLR:oligo-Myd88:TIRAP:p-IRAK4 complex
findings: []
- id: Reactome:R-HSA-166363
title: TRAF6 binds to hp- IRAK1
findings: []
- id: Reactome:R-HSA-2201316
title: Activated TLR2/4 interacts with MAL (TIRAP)
findings: []
- id: Reactome:R-HSA-2201322
title: TIRAP is phosphorylated by BTK
findings: []
- id: Reactome:R-HSA-2262775
title: Dissociation of p-IRAK2:TRAF6 from the activated
TLR:oligo-Myd88:TIRAP:p-IRAK4 complex
findings: []
- id: Reactome:R-HSA-2262777
title: TRAF6 binds to p-IRAK2
findings: []
- id: Reactome:R-HSA-2559414
title: Activated TLR2/4:TIRAP interacts with BTK
findings: []
- id: Reactome:R-HSA-266204
title: Association of HMGB1/HMGB2 with chromatin
findings: []
- id: Reactome:R-HSA-5432825
title: HMGB1 binds TLR4:LY96
findings: []
- id: Reactome:R-HSA-5602353
title: Defective IRAK4 does not bind MyD88:MAL:BTK:activated TLR2/4
findings: []
- id: Reactome:R-HSA-5602383
title: Defective MyD88 does not oligomerize within the activated TLR2/4
complex
findings: []
- id: Reactome:R-HSA-5602606
title: Defective MyD88 does not bind MAL(TIRAP):TLR2/4
findings: []
- id: Reactome:R-HSA-6798748
title: Exocytosis of secretory granule lumen proteins
findings: []
- id: Reactome:R-HSA-6800434
title: Exocytosis of ficolin-rich granule lumen proteins
findings: []
- id: Reactome:R-HSA-6804099
title: HMGB1 binds LTP
findings: []
- id: Reactome:R-HSA-6804100
title: HMGB1 binds LPS
findings: []
- id: Reactome:R-HSA-6805981
title: HMGB1 release from cells
findings: []
- id: Reactome:R-HSA-879411
title: Advanced glycosylation end product-specific receptor (AGER/RAGE) is a
multiligand receptor
findings: []
- id: Reactome:R-HSA-937022
title: IRAK4 autophosphorylation in the complex with activated
TLR:MyD88:TIRAP
findings: []
- id: Reactome:R-HSA-937059
title: Phosphorylation of IRAK2 bound to the activated IRAK4:MyD88
oligomer:TIRAP:activated TLR complex
findings: []
- id: Reactome:R-HSA-937079
title: MyD88 oligomerization within the complex of activated TLR:TIRAP:MyD88
findings: []
- id: Reactome:R-NUL-997411
title: AGER binds rat ERK1/2
findings: []
- id: file:human/HMGB1/HMGB1-deep-research-falcon.md
title: Deep research report on HMGB1
findings: []