Affinage

HMGB1

High mobility group protein B1 · UniProt P09429

Round 2 corrected
Length
215 aa
Mass
24.9 kDa
Annotated
2026-04-28
130 papers in source corpus 38 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HMGB1 is a multifunctional chromatin-associated protein that acts both as an architectural DNA-binding factor in the nucleus and as a damage-associated molecular pattern (DAMP) cytokine in the extracellular space. Its two HMG-box domains unwind and bend DNA (inducing bend angles of 80–95°), preferentially recognize distorted DNA structures such as cisplatin adducts and four-way junctions, and facilitate assembly of nucleoprotein complexes with p53, topoisomerase IIα, and Rel-family transcription factors (PMID:628842, PMID:1425584, PMID:9472015, PMID:17636313). Active secretion from monocytes/macrophages occurs via hyperacetylation of nuclear localization signals followed by lysosomal exocytosis, with PARP-1-mediated PARylation, calcium-dependent phosphorylation, and lactate-driven lactylation serving as additional regulatory inputs; passive release occurs from necrotic or pyroptotic—but not apoptotic—cells, where histone hypoacetylation retains HMGB1 on chromatin (PMID:14532127, PMID:12110890, PMID:25392528, PMID:34363018). Extracellular HMGB1 cytokine activity requires a specific redox state—a C23–C45 disulfide bond with C106 as a free thiol—for TLR4 binding and NF-κB-dependent TNF induction, while the fully reduced form heterodimerizes with CXCL12 for CXCR4-dependent leukocyte recruitment, and HMGB1 delivers LPS into lysosomes via RAGE to activate caspase-11 pyroptosis; in the cytoplasm, HMGB1 promotes autophagy by displacing Bcl-2 from Beclin1 in a C23/C45-disulfide- and C106-dependent manner (PMID:34098868, PMID:22370717, PMID:30314759, PMID:20819940).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1978 High

    The earliest mechanistic question—whether HMG1 directly alters DNA topology—was answered by demonstrating that HMG1 reduces the linking number of circular DNA, establishing it as a DNA-unwinding architectural factor.

    Evidence Topoisomerase-based linking number assay with circular DNA in vitro

    PMID:628842

    Open questions at the time
    • Unwinding angle per molecule not yet quantified
    • Functional relevance in chromatin context unknown
    • No information on the role of HMG-box domains individually
  2. 1987 Medium

    The question of whether redox state affects HMG1 chromatin function was resolved by showing that only reduced HMG1 forms a ternary complex with H1 and DNA, introducing the concept that cysteine redox chemistry regulates HMG1 activity.

    Evidence Circular dichroism spectroscopy of DNA–H1–HMG1 complexes with oxidized vs. reduced protein

    PMID:3804996

    Open questions at the time
    • Identity of the specific cysteines involved not determined
    • In vivo relevance of redox regulation not tested
    • Single biophysical method (CD) without orthogonal confirmation
  3. 1992 High

    The nature of HMG1's DNA-structure recognition was established: HMG1 preferentially binds distorted DNA structures including cisplatin intrastrand cross-links (Kd ~370 nM) and four-way junctions, defining HMG-box interaction as primarily structure-specific rather than sequence-specific.

    Evidence Binding assays with cisplatin-modified DNA and four-way junction DNA substrates using recombinant protein

    PMID:1425584 PMID:1566071

    Open questions at the time
    • Physiological role of cisplatin-DNA recognition unclear
    • Whether structure specificity governs chromatin localization in vivo not known
    • Contribution of individual HMG-box domains (A vs. B) not resolved
  4. 1998 High

    The question of whether HMG1 could serve as a transcriptional cofactor was answered by showing it directly binds p53 and enhances p53-mediated transactivation, establishing HMGB1 as a nucleoprotein complex assembly factor for sequence-specific transcription factors.

    Evidence Biochemical purification from HeLa extracts, recombinant pull-down, in vitro DNA-binding assay, and reporter assays

    PMID:9472015

    Open questions at the time
    • Whether HMGB1-p53 interaction occurs on endogenous promoters in vivo not shown
    • Mechanism by which HMGB1 stimulates p53 DNA binding not structurally resolved
    • Generalizability to other transcription factors beyond p53 not yet demonstrated
  5. 1999 High

    Quantitative biophysical studies defined the DNA-bending mechanism: domain B bends cisplatin-DNA by 80–95° with fast kinetics (kon ~10⁹ M⁻¹s⁻¹), while intramolecular NMR and calorimetry showed the acidic tail interacts with HMG-box domains to regulate DNA-structure selectivity.

    Evidence FRET, stopped-flow fluorescence, differential scanning calorimetry, circular dichroism, and NMR spectroscopy

    PMID:10102997 PMID:10212205

    Open questions at the time
    • No high-resolution structure of full-length HMGB1 bound to DNA
    • Whether the tail-box interaction is regulated by post-translational modifications unknown
    • Relative contributions of domains A and B to bending in full-length context unclear
  6. 2002 High

    The dual extracellular life of HMGB1 was established: active secretion from monocytes/macrophages occurs via non-classical lysosomal exocytosis, while passive release distinguishes necrosis (inflammatory, HMGB1 released) from apoptosis (tolerogenic, HMGB1 retained by hypoacetylated chromatin).

    Evidence Immunofluorescence, EM, subcellular fractionation, HMGB1 KO necrotic cells, HDAC inhibition experiments

    PMID:12110890 PMID:12231511

    Open questions at the time
    • Specific acetylation sites governing chromatin retention not mapped
    • Mechanism of HMGB1 loading into secretory lysosomes not defined
    • Whether necrotic HMGB1 release requires active cellular processes unknown
  7. 2003 High

    The molecular mechanism of active HMGB1 secretion was defined: hyperacetylation of lysines within nuclear localization sequences causes nuclear-to-cytoplasmic redistribution and accumulation in secretory lysosomes, with MS-based mapping of specific acetylation sites.

    Evidence Mass spectrometry acetylation mapping, forced hyperacetylation, subcellular fractionation in activated macrophages

    PMID:14532127

    Open questions at the time
    • Enzymes responsible for HMGB1 hyperacetylation in activated macrophages not identified
    • Whether hyperacetylation is sufficient without additional PTMs not fully resolved
    • Pathway from cytosol to secretory lysosome not defined
  8. 2005 High

    The receptor basis for extracellular HMGB1 signaling was established by demonstrating direct binding to TLR2 and TLR4 on macrophages, activating NF-κB-dependent transcription.

    Evidence FRET and co-immunoprecipitation for HMGB1–TLR interaction, NF-κB reporter assay in HEK-293 cells

    PMID:16267105

    Open questions at the time
    • Binding interface between HMGB1 and TLR4 not structurally resolved
    • Role of HMGB1 redox state in receptor selectivity not yet addressed
    • Relative contribution of TLR2 vs TLR4 in different cell types unknown
  9. 2008 High

    The redox-based switch between immunostimulatory and tolerogenic HMGB1 was explained: caspase-dependent ROS during apoptosis oxidize HMGB1 to an inactive form, while reduced or partially oxidized HMGB1 from necrotic cells remains inflammatory.

    Evidence Caspase/ROS inhibition, site-directed mutagenesis of oxidation sites, in vivo tolerance assays

    PMID:18631454

    Open questions at the time
    • Specific oxidized residues and their structural consequences not fully characterized
    • Whether oxidized HMGB1 has any positive signaling role unknown
    • Quantitative thresholds of ROS required for HMGB1 inactivation not determined
  10. 2010 High

    Three major functional axes were resolved: (1) cytokine activity requires TLR4 binding at C106 (SPR-confirmed), (2) cytoplasmic HMGB1 promotes autophagy by displacing Bcl-2 from Beclin1 in a C106- and C23/C45-disulfide-dependent manner, and (3) HMGB1 modulates base excision repair sub-pathway choice.

    Evidence SPR binding, C106A mutagenesis, TLR4 KO macrophages, synthetic peptide, Co-IP with Beclin1, HMGB1-KO autophagy assays, in vitro BER reconstitution

    PMID:20123074 PMID:20547845 PMID:20819940

    Open questions at the time
    • Structural basis of HMGB1–Beclin1 interaction not resolved
    • How intracellular redox environment is sensed to toggle HMGB1 function unclear
    • BER modulation validated only in vitro
  11. 2012 High

    Multiple extracellular HMGB1 partnerships were defined: HMGB1 forms a heterocomplex with CXCL12 (NMR-characterized) that recruits leukocytes via CXCR4, interacts with TIM-3 on DCs to suppress nucleic acid sensing, and nuclear HMGB1–p53 complex regulates the autophagy–apoptosis balance.

    Evidence NMR, SPR, FRET for CXCL12/CXCR4; Co-IP for TIM-3; reciprocal KO epistasis for p53–HMGB1 complex

    PMID:22345153 PMID:22370717 PMID:22842346

    Open questions at the time
    • How the HMGB1–CXCL12 stoichiometry is regulated in vivo unknown
    • Structural basis of TIM-3–HMGB1 interaction not defined
    • Whether p53 and Beclin1 compete for the same HMGB1 pool not tested
  12. 2014 High

    PARP-1 was identified as an upstream regulator of HMGB1 secretion: PARylation of HMGB1 primes subsequent acetylation, and PARP-1 increases the HAT/HDAC ratio to facilitate nuclear-to-cytoplasmic translocation.

    Evidence In vitro PARylation/acetylation assays, PARP-1 genetic depletion and pharmacological inhibition, subcellular fractionation

    PMID:25392528

    Open questions at the time
    • Specific PARylation sites on HMGB1 not mapped
    • Whether PARylation is required in all cell types secreting HMGB1 unknown
    • Interplay between PARylation, phosphorylation, and lactylation not integrated
  13. 2018 High

    A new receptor-mediated function was established: hepatocyte-released HMGB1 binds LPS and delivers it into macrophage lysosomes via RAGE, then permeabilizes lysosomal membranes at acidic pH to allow cytosolic LPS access and caspase-11-dependent pyroptosis.

    Evidence Hepatocyte-specific HMGB1 KO, RAGE KO, lysosomal permeability assays, caspase-11 activation, endotoxemia and CLP models

    PMID:30314759

    Open questions at the time
    • Molecular mechanism of HMGB1-mediated lysosomal membrane permeabilization unknown
    • Stoichiometry of HMGB1–LPS complex not determined
    • Whether this pathway operates for other microbial products beyond LPS not tested
  14. 2021 High

    The precise redox code for HMGB1 cytokine activity was defined: the C23–C45 disulfide bond plus free C106 thiol is required for TLR4 binding and NF-κB/TNF induction; fully reduced or further oxidized forms are inactive. Lactylation was identified as a new PTM regulating HMGB1 release via p300/CBP and exosomes.

    Evidence Defined redox isoforms and C45A mutant in primary human macrophages; MCT/p300/GPR81 inhibition, exosome isolation, in vivo sepsis

    PMID:34098868 PMID:34363018

    Open questions at the time
    • No crystal structure of the disulfide isoform bound to TLR4/MD-2
    • In vivo kinetics of redox state transitions not measured
    • How lactylation and acetylation are coordinated on the same HMGB1 molecule unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the high-resolution structural basis of full-length HMGB1 interaction with TLR4/MD-2, how intracellular redox sensing toggles HMGB1 between its nuclear, autophagic, and secretory pools, the integration of multiple PTMs (acetylation, PARylation, phosphorylation, lactylation, methylation) into a unified secretion code, and the physiological significance of HMGB1's BER-modulatory activity in vivo.
  • No co-crystal structure of HMGB1 with TLR4/MD-2 complex
  • Unified PTM code for HMGB1 secretion not established
  • BER modulation not validated in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 6 GO:0048018 receptor ligand activity 4 GO:0098772 molecular function regulator activity 3 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 7 GO:0005576 extracellular region 6 GO:0005829 cytosol 4 GO:0005764 lysosome 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-168256 Immune System 8 R-HSA-162582 Signal Transduction 4 R-HSA-4839726 Chromatin organization 3 R-HSA-9612973 Autophagy 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 2
Partners
AGERBECN1CXCL12HAVCR2TLR2TLR4TOP2ATP53
Complex memberships
HMGB1–Beclin1 complexHMGB1–CXCL12 heterocomplexHMGB1–p53 complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1978 HMG1 and HMG2 reduce the linking number of circular DNA when covalent closure occurs in their presence, indicating these proteins unwind the DNA double helix or induce supercoiling. Topoisomerase-based linking number assay with circular DNA Science High 628842
1979 HMG1 and HMG2 unwind the DNA double helix by local denaturation of base pairs; HMG1 has higher affinity for single-stranded DNA than double-stranded DNA, with net unwinding angles of 22° and 26° per molecule for HMG1 and HMG2, respectively. Melting absorption spectroscopy, competition unwinding experiments Nucleic acids research High 226939
1987 HMG1 modulates histone H1-induced condensation of DNA; the ternary DNA-H1-HMG1 complex requires the reduced (not disulfide) form of HMG1, revealing that the redox state of HMG1's cysteine residues affects its chromatin-compacting function. Circular dichroism spectroscopy of DNA-protein complexes The Journal of biological chemistry Medium 3804996
1992 Recombinant rat HMG1 binds specifically (Kd ~370 nM) to DNA containing cisplatin d(GpG) or d(ApG) intrastrand cross-links but not to DNA modified by therapeutically inactive platinum analogs, establishing HMG1 as a specific sensor of cisplatin-induced DNA damage. Binding assay with recombinant protein and cisplatin-modified DNA Science High 1566071
1992 HMG1 and the HMG box of SRY recognize four-way junction DNAs (which contain sharp angles of ~60° and 120°), and SRY produces a sharp bend when bound to its linear duplex target AACAAAG; HMG-box–DNA interaction is predominantly structure-specific. Gel mobility shift assay with four-way junction DNA, DNA binding assays The EMBO journal High 1425584
1998 HMG-1 directly interacts with p53 in vitro and stimulates p53 DNA binding; it enhances p53-mediated transactivation in vivo and promotes assembly of higher-order p53 nucleoprotein structures, acting via a mechanism distinct from other p53 activators (including stimulating the constitutively active p53Δ30 mutant). Biochemical purification from HeLa nuclear extracts, recombinant protein pull-down, in vitro DNA-binding assay, transient transfection reporter assay Genes & development High 9472015
1999 HMG1 domain B binds cisplatin-modified DNA with a Kd of ~60 nM and induces a DNA bend angle of 80–95°, as measured by FRET; kinetic parameters kon = 1.1 × 10⁹ M⁻¹s⁻¹ and koff = 30 s⁻¹ were determined by stopped-flow fluorescence. Fluorescence resonance energy transfer (FRET), stopped-flow fluorescence spectroscopy, fluorescence titration The Journal of biological chemistry High 10212205
1999 Drosophila DSP1, an HMG-1/2-like protein, binds DNA cooperatively with NF-κB, p50, and the Rel domain of Dorsal; direct protein–protein interactions between DSP1 and Rel proteins occur in the absence of DNA, and DSP1 modulates Dorsal transcriptional activation in a promoter-specific manner. DNA-binding assay, protein–protein interaction assays, transient transfection reporter assay in HeLa cells Proceedings of the National Academy of Sciences of the United States of America Medium 10485885
1999 Within full-length HMG1, the acidic C-terminal tail (domain C) interacts with one of the two HMG-box domains (A or B) but the two HMG-box domains do not interact with each other; this intramolecular interaction stabilizes the protein with an estimated free energy of ~2.5 kcal/mol. Differential scanning calorimetry, circular dichroism of isolated and full-length domains European journal of biochemistry High 10102997
2002 HMGB1 is secreted by activated monocytes and macrophages via a non-classical, vesicle-mediated secretory pathway involving lysosomal exocytosis; it redistributes from the nucleus to cytoplasmic endolysosomal compartments upon monocyte activation, and secretion is triggered by lysophosphatidylcholine (a late-inflammation mediator) rather than ATP (which triggers early IL-1β secretion). Immunofluorescence, electron microscopy, subcellular fractionation, stimulus-specific secretion assays EMBO reports High 12231511
2002 HMGB1 is passively released by necrotic but not apoptotic cells; in apoptotic cells, HMGB1 is retained in chromatin due to generalized histone deacetylation, but inhibiting deacetylation allows its release and inflammatory activity. Hmgb1−/− necrotic cells have greatly reduced ability to promote inflammation. Knockout cell lines, genetic deletion, chromatin fractionation, histone deacetylase inhibition Nature High 12110890
2003 Monocytes and macrophages hyperacetylate HMGB1 on lysine residues within nuclear localization sequences upon LPS activation; this hyperacetylation causes HMGB1 to redistribute from nucleus to cytosol and then concentrate in secretory lysosomes for release by exocytosis. Forced hyperacetylation in resting macrophages is sufficient to relocalize HMGB1 to cytosol. Mass spectrometry-based acetylation mapping, pharmacological forced acetylation, subcellular fractionation, immunofluorescence The EMBO journal High 14532127
2005 HMGB1 directly interacts with TLR2 and TLR4 (but not RAGE) on macrophage surfaces, as demonstrated by FRET and co-immunoprecipitation; HMGB1 induces cellular activation and NF-κB-dependent transcription through TLR2 or TLR4. Fluorescence resonance energy transfer (FRET), co-immunoprecipitation, NF-κB reporter assay in HEK-293 cells American journal of physiology. Cell physiology High 16267105
2007 The acidic C-terminal tail of HMGB1 interacts directly with its own N-terminal HMG-box domains (intramolecular interaction confirmed by NMR); this interaction is competed more efficiently by four-way junction DNA than by linear DNA, and mutations in the N-terminal region that disrupt tail binding abolish HMGB1's ability to distinguish structured from linear DNA. NMR spectroscopy, competition DNA-binding assays, mutagenesis Biochemical and biophysical research communications High 17585880
2007 HMGB1 physically interacts with topoisomerase IIα and stimulates its catalytic activities (catenation, relaxation, decatenation, and DNA cleavage); both HMG-box domains of HMGB1 are required for this stimulation; HMGB1 enhances topo IIα binding to DNA and ATP hydrolysis. Co-immunoprecipitation, in vitro topoisomerase activity assays (catenation, relaxation, decatenation), domain mutagenesis Nucleic acids research High 17636313
2008 Caspase-dependent ROS production during apoptosis oxidizes HMGB1, inactivating its immunostimulatory activity; blocking ROS or mutating sites of HMGB1 oxidation prevents tolerance induction by apoptotic cells. This establishes the mechanism by which apoptotic cell death is tolerogenic (oxidized HMGB1) versus necrotic cell death being inflammatory (reduced HMGB1). Genetic and pharmacological inhibition of caspases and ROS, site-directed mutagenesis of HMGB1 oxidation sites, in vivo tolerance assays Immunity High 18631454
2010 HMGB1 acts as a critical pro-autophagic protein by directly binding Beclin1 and displacing Bcl-2 from it; cytosolic translocation of HMGB1 (promoted by ROS) enhances autophagic flux. Cysteine 106 mutation promotes cytosolic localization and sustained autophagy, while the intramolecular disulfide bridge (C23/C45) is required for Beclin1 binding. Co-immunoprecipitation, site-directed mutagenesis (C106A, C23/45 mutants), autophagy flux assays, KO cell lines (HMGB1−/−, Beclin1−/−) The Journal of cell biology High 20819940
2010 TLR4 is required for HMGB1-dependent activation of macrophage TNF release; HMGB1 binds specifically to TLR4 (confirmed by surface plasmon resonance), and this binding requires cysteine 106 of HMGB1. A synthetic 20-mer peptide containing C106 from the B box mediates TLR4-dependent macrophage activation; C106 mutation prevents both TLR4 binding and cytokine induction. Surface plasmon resonance, site-directed mutagenesis (C106A), TLR4 KO macrophages, synthetic peptide assay, TNF ELISA Proceedings of the National Academy of Sciences of the United States of America High 20547845
2010 HMGB1 acts as a cofactor that regulates base excision repair (BER) sub-pathways: it inhibits single-nucleotide BER and stimulates long-patch BER by modulating activities of BER enzymes, and this can promote trinucleotide repeat instability. In vitro BER reconstitution assays with recombinant HMGB1, cross-linking studies Biochimica et biophysica acta Medium 20123074
2012 HMGB1 and p53 form a complex that regulates the balance between autophagy and apoptosis: p53 is a negative regulator of the HMGB1/Beclin1 complex, and knockout of p53 increases cytosolic HMGB1 and autophagy while knockout of HMGB1 increases cytosolic p53 and decreases autophagy. The HMGB1/p53 complex affects cytoplasmic localization of the reciprocal partner. Co-immunoprecipitation, p53 and HMGB1 KO cell lines (HCT116, MEFs), subcellular fractionation, autophagy assays Cancer research High 22345153
2012 PKR (double-stranded RNA-dependent protein kinase) physically interacts with multiple inflammasome components (NLRP3, NLRP1, NLRC4, AIM2) and is required for inflammasome activation and HMGB1 release; PKR autophosphorylation in a cell-free system with recombinant NLRP3, ASC, and pro-caspase-1 reconstitutes inflammasome activity. Co-immunoprecipitation, PKR genetic deletion and pharmacological inhibition, cell-free reconstitution of inflammasome with recombinant components, peritonitis model Nature High 22801494
2012 HMGB1 forms a heterocomplex with CXCL12 (characterized by NMR and surface plasmon resonance) that acts exclusively through CXCR4 to recruit inflammatory cells; the heterocomplex promotes different CXCR4 conformational rearrangements than CXCL12 alone (by FRET), and only the all-thiol (fully reduced) redox form of HMGB1 can bind CXCL12. NMR spectroscopy, surface plasmon resonance, FRET, in vivo air pouch and muscle injury models, AMD3100 inhibition The Journal of experimental medicine High 22370717
2012 HMGB1 binds directly to influenza virus nucleoprotein (NP) via its HMG-box A domain (in the absence of viral RNA), associates with NP in nuclei of infected cells, promotes viral polymerase activity, and is required for efficient viral growth; glycyrrhizin (which reduces HMGB1-DNA binding) inhibits influenza polymerase activity. Phage display selection, direct binding assay with purified NP, co-immunoprecipitation from infected cells, viral polymerase activity assay, domain truncation analysis Journal of virology High 22696656
2012 TIM-3 on tumor-infiltrating dendritic cells interacts with HMGB1 via a galectin-9-independent mechanism to interfere with recruitment of nucleic acids into DC endosomes, thereby suppressing TLR- and cytosolic sensor-mediated innate immune responses and diminishing therapeutic efficacy of DNA vaccination and chemotherapy. Co-immunoprecipitation (TIM-3/HMGB1), endosomal nucleic acid recruitment assay, galectin-9 KO controls, in vivo tumor models with DNA vaccination and chemotherapy Nature immunology High 22842346
2013 The C-terminal acidic tail of HMGB1 directly interacts with the N-terminal unstructured tail of histone H3 (by NMR spectroscopy), and this interaction is extensive for both peptides without resulting in significant secondary structure acquisition; this interaction may position HMGB1 on linker DNA adjacent to nucleosomes. NMR spectroscopy, pull-down assays with H3 peptides Nucleic acids research High 24157840
2014 PARP-1 regulates LPS-induced HMGB1 release from macrophages via two mechanisms: (1) PARylating HMGB1 to facilitate subsequent acetylation, and (2) increasing the HAT/HDAC activity ratio; PARylated HMGB1 remains nuclear while acetylated HMGB1 localizes to the cytoplasm. PARP inhibition or PARP-1 depletion suppresses LPS-induced HMGB1 translocation and release. Genetic PARP-1 depletion, pharmacological PARP inhibition, in vitro PARylation/acetylation enzymatic assay, subcellular fractionation, import assay Journal of immunology High 25392528
2015 Ethyl pyruvate inhibits HMGB1 phosphorylation and release by directly chelating calcium, thereby suppressing Ca²⁺-mediated kinase activation (PKCα and CaMKIV) that phosphorylates HMGB1 prior to secretion. Calcium imaging, fluorometric Ca²⁺ scavenging assay with Mag-Fura-2, kinase activation assays, HMGB1 phosphorylation and secretion measurements in BV2 cells Molecular medicine Medium 25333921
2016 Haptoglobin directly binds HMGB1 and delivers HMGB1-haptoglobin complexes to CD163 on macrophages; this complex elicits anti-inflammatory responses (heme oxygenase-1 induction, IL-10 production) in WT but not CD163-deficient macrophages. Genetic disruption of haptoglobin or CD163 enhances mortality in sepsis. Affinity binding assay, CD163 KO macrophages, haptoglobin KO mice, sepsis survival model JCI insight High 27294203
2017 Metformin directly binds the C-terminal acidic tail of HMGB1 (identified by affinity purification with biotinylated metformin analogue); metformin inhibits inflammatory responses induced by full-length HMGB1 but not by HMGB1 lacking the acidic tail, both in vitro and in vivo in an acetaminophen-induced liver injury model. Affinity purification with biotinylated metformin analogue, HMGB1 tail deletion mutant functional assays, in vitro cytokine assays, in vivo liver injury model The Journal of biological chemistry High 28373282
2018 Hepatocyte-released HMGB1 is required for caspase-11-dependent pyroptosis and lethality in endotoxemia/sepsis; mechanistically, HMGB1 binds LPS and mediates its internalization into macrophage/endothelial cell lysosomes via RAGE, then permeabilizes lysosomal membranes in acidic conditions, allowing LPS to leak into the cytosol for caspase-11 activation. Hepatocyte-specific HMGB1 KO, RAGE KO, neutralizing antibodies, lysosomal permeability assays, caspase-11 activation assays, endotoxemia and cecal ligation and puncture models Immunity High 30314759
2019 HMGB1 is released by ferroptotic cells in an autophagy-dependent manner; autophagy-mediated HDAC inhibition promotes HMGB1 acetylation leading to its release during ferroptosis. AGER (RAGE), but not TLR4, is required for HMGB1-mediated inflammation in macrophages responding to ferroptotic cells. ATG5/ATG7 KO cells, pharmacological autophagy inhibition (bafilomycin A1, chloroquine), HDAC inhibition, ferroptosis inducers (erastin, RSL3, sorafenib, FIN56), AGER/TLR4 genetic ablation Biochemical and biophysical research communications High 30686534
2020 HMGB1 release after inflammasome activation in bone marrow-derived macrophages occurs only under conditions causing cell lysis (pyroptosis); when pyroptosis is prevented, HMGB1 is not released despite inflammasome activation and IL-1β secretion. Gasdermin D KO mice secrete HMGB1 normally during endotoxemia, demonstrating that HMGB1 release in vivo is inflammasome-independent and requires cellular rupture. Gasdermin D KO macrophages and mice, LPS stimulation, inflammasome activation assays, HMGB1/IL-1β secretion measurement, pyroptosis prevention Nature communications High 32917873
2021 The cytokine activity of HMGB1 requires an intramolecular disulfide bond between C23 and C45 while C106 must remain as a free thiol; fully reduced HMGB1 fails to activate NF-κB or induce TNF-α, and mutation of C45 to alanine abolishes cytokine induction. Further oxidation of the disulfide isoform also inactivates HMGB1. Redox-modified recombinant HMGB1 preparations, C45A point mutant, primary human macrophages and RAW264.7 cells, NF-κB p65 phosphorylation ELISA, TNF-α ELISA Molecular medicine High 34098868
2021 Lactate promotes HMGB1 lactylation in macrophages via a p300/CBP-dependent mechanism after uptake through monocarboxylate transporters; lactate also stimulates HMGB1 acetylation via Hippo/YAP-mediated SIRT1 suppression and β-arrestin2-mediated p300/CBP nuclear recruitment via GPR81. The lactylated/acetylated HMGB1 is released via exosomes and increases endothelium permeability. MCT inhibition, p300/CBP inhibition, GPR81 signaling inhibition, SIRT1 and YAP pathway analysis, exosome isolation, endothelial permeability assay, in vivo polymicrobial sepsis model Cell death and differentiation High 34363018
2021 YAP promotes HMGB1 transcription and nuclear-to-cytoplasmic translocation in glioblastoma cells; HMGB1 mediates YAP-induced autophagy and tumor growth, and knockdown of HMGB1 abolishes the pro-autophagic and pro-tumorigenic effects of YAP. YAP overexpression/knockdown, HMGB1 knockdown, iTRAQ quantitative proteomics, GFP-LC3 imaging, transmission electron microscopy, autophagy flux assay, xenograft tumor model Journal of experimental & clinical cancer research Medium 33726796
2022 During intracerebral hemorrhage, HMGB1 translocates from nucleus to cytoplasm and upregulates TLR4 and MyD88 expression; the HMGB1/TLR4/MyD88 axis promotes autophagy (LC3B, Beclin1, Atg5 upregulation), and autophagy in turn promotes neuroinflammation and apoptosis. siRNA knockdown of HMGB1 or TLR4, or autophagy inhibition with 3-MA, alleviated inflammation and neurological deficits. siRNA knockdown of HMGB1 and TLR4, autophagy inhibitor (3-MA) and activator (rapamycin), Western blotting, immunofluorescence, TUNEL staining, neurological scoring in rat ICH model Brain research Medium 35820449
2022 HMGB1 secretion and release is regulated by distinct post-translational modifications (acetylation mobilizes HMGB1 from nucleus to cytoplasm; ADP-ribosylation, phosphorylation, and methylation also contribute) and by the molecular machinery of different cell death modalities (apoptosis, pyroptosis, necroptosis, alkaliptosis, ferroptosis), with autophagy playing a critical role in ferroptosis-associated release. Review integrating mechanistic studies of PTMs and cell death pathway-specific release mechanisms Experimental & molecular medicine Medium 35217834
2020 HMGB1 regulates ACE2 expression and is critical for SARS-CoV-2, SARS-CoV-1, and NL63 entry; identified by genome-wide CRISPR screen in Vero-E6 cells, validated by showing that HMGB1-targeting small-molecule antagonists inhibit SARS-CoV-2 infection in monkey and human cells. Genome-wide CRISPR screen, HMGB1 KO validation, ACE2 expression assay, small-molecule inhibitor treatment, viral infection assays in multiple cell types Cell High 33147444

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 3418 12110890
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2006 Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Molecular cell 1260 16916647
2010 HMGB1 and RAGE in inflammation and cancer. Annual review of immunology 1213 20192808
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2003 Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. The EMBO journal 1045 14532127
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2010 Endogenous HMGB1 regulates autophagy. The Journal of cell biology 813 20819940
2008 Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication. Cell 787 18854154
2014 HMGB1 in health and disease. Molecular aspects of medicine 782 25010388
1999 N(epsilon)-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression. The Journal of biological chemistry 780 10531386
2002 The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway. EMBO reports 759 12231511
2005 High mobility group box 1 protein interacts with multiple Toll-like receptors. American journal of physiology. Cell physiology 756 16267105
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nature immunology 705 22842346
2012 A census of human soluble protein complexes. Cell 689 22939629
2010 A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release. Proceedings of the National Academy of Sciences of the United States of America 677 20547845
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2012 Novel role of PKR in inflammasome activation and HMGB1 release. Nature 639 22801494
2022 The mechanism of HMGB1 secretion and release. Experimental & molecular medicine 637 35217834
2021 Lactate promotes macrophage HMGB1 lactylation, acetylation, and exosomal release in polymicrobial sepsis. Cell death and differentiation 632 34363018
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