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.
Definition: Binding to an unfolded or misfolded protein to prevent its aggregation without actively catalyzing refolding. The holdase maintains the client protein in a soluble, folding-competent state. This is mechanistically distinct from foldase activity (GO:0044183) and from carrier-holdase activity (GO:0140309).
Justification: HMGB1: recombinant HMGB1 suppresses chemically and heat-induced aggregation of model substrates in vitro and binds expanded polyglutamine, reducing polyQ aggregation in cells; this is a secondary, chaperone-like activity of a chromatin protein. Obsolete GO:0051082 captured binding only; GO:0044183 requires assisting folding, and GO:0140309 (relabelled 'unfolded protein holdase activity') keeps a carrier-specific definition requiring escort to an acceptor molecule or location, which is not demonstrated here. See go-ontology#30552. GO:0051787 misfolded protein binding is live but, like the obsolete GO:0051082, records client binding only and not the suppression of aggregation, so it does not capture the activity. The proposed parent is the molecular_function root because GO has no general chaperone-activity grouping term: GO:0044183 protein folding chaperone is itself a direct child of GO:0003674.
Parent term: molecular_function
Supporting Evidence:
| 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) file:human/HMGB1/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. This IPI row records binding to huntingtin (WITH/FROM UniProtKB:P42858), and the paper shows HMGB1 binding expanded polyglutamine, an aggregation-prone misfolded client, so misfolded protein binding is the informative binding term that IPI supports. The same paper's anti-aggregation assays support the proposed holdase chaperone activity term (see proposed_new_terms), which is an activity claim rather than a binding claim. Proposed replacements: misfolded protein binding Supporting Evidence: PMID:23303669 HMGB1 directly interacted with polyQ on immunofluorescence and coimmunoprecipitation assay |
| 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 ... | KEEP AS NON CORE | Summary: HMGB1-CXCL12 complex induces calcium signaling via CXCR4. Reason: Real but non-core: the cytosolic calcium increase is a downstream consequence of extracellular HMGB1-CXCL12 acting through the CXCR4 receptor, not a core function of HMGB1 (whose core roles are nuclear chromatin architecture / DNA bending and extracellular DAMP signaling). Surfaced by the ASSAY_TO_FUNCTION analysis (indirect ligand effect on a calcium readout). 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-Ξ²-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-Ξ²-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 |
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