HMGB1

Summary

HMGB1 (high mobility group box 1, HGNC:4983) is a protein-coding gene on chromosome 13q12.3, encoding High mobility group protein B1 (P09429). Multifunctional redox sensitive protein with various roles in different cellular compartments. It is a selective cancer dependency (DepMap: 83.4% of cell lines).

This gene encodes a protein that belongs to the High Mobility Group-box superfamily. The encoded non-histone, nuclear DNA-binding protein regulates transcription, and is involved in organization of DNA. This protein plays a role in several cellular processes, including inflammation, cell differentiation and tumor cell migration. Multiple pseudogenes of this gene have been identified. Alternative splicing results in multiple transcript variants that encode the same protein.

Source: NCBI Gene 3146 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 24
• Clinical variants (ClinVar): 41 total — 4 pathogenic, 5 likely-pathogenic
• Druggable target: yes — 7 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 83.4% of screened cell lines
• MANE Select transcript: NM_002128

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4983
Approved symbol	HMGB1
Name	high mobility group box 1
Location	13q12.3
Locus type	gene with protein product
Status	Approved
Aliases	HMG3, SBP-1, DKFZp686A04236
Ensembl gene	ENSG00000189403
Ensembl biotype	protein_coding
OMIM	163905
Entrez	3146

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 38 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000326004, ENST00000339872, ENST00000341423, ENST00000399489, ENST00000399494, ENST00000405805, ENST00000468384, ENST00000490788, ENST00000897840, ENST00000897841, ENST00000897842, ENST00000897843, ENST00000897844, ENST00000897845, ENST00000897846, ENST00000897847, ENST00000897848, ENST00000897849, ENST00000897850, ENST00000897851, ENST00000897852, ENST00000897853, ENST00000897854, ENST00000897855, ENST00000897856, ENST00000897857, ENST00000927781, ENST00000927782, ENST00000927783, ENST00000927784, ENST00000927785, ENST00000927786, ENST00000927787, ENST00000927788, ENST00000927789, ENST00000927790, ENST00000927791, ENST00000927792, ENST00000970317, ENST00000970318

RefSeq mRNA: 7 — MANE Select: NM_002128 NM_001313892, NM_001313893, NM_001363661, NM_001370339, NM_001370340, NM_001370341, NM_002128

CCDS: CCDS86347, CCDS9335

Canonical transcript exons

ENST00000341423 — 5 exons

Exon	Start	End
ENSE00000906655	30463207	30463352
ENSE00001381337	30462538	30462712
ENSE00001384053	30463531	30463694
ENSE00001485486	30465796	30465936
ENSE00003747687	30456704	30461533

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 99.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 107.8037 / max 2260.2992, expressed in 1823 samples.

FANTOM5 promoters (19 alternative TSS)

Promoter ID	TPM avg	Samples expressed
136648	76.3561	1820
136654	6.3477	1360
136647	5.0309	1506
136638	4.0398	1306
136645	3.5541	1194
136640	2.4582	955
136651	2.1003	995
136644	1.8981	902
136643	1.8397	809
136650	1.5995	365

Top tissues by expression

256 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.81	gold quality
ganglionic eminence	UBERON:0004023	99.73	gold quality
cortical plate	UBERON:0005343	99.64	gold quality
calcaneal tendon	UBERON:0003701	99.53	gold quality
smooth muscle tissue	UBERON:0001135	99.45	gold quality
body of uterus	UBERON:0009853	99.44	gold quality
vermiform appendix	UBERON:0001154	99.43	gold quality
trabecular bone tissue	UBERON:0002483	99.43	gold quality
rectum	UBERON:0001052	99.42	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.39	gold quality
endocervix	UBERON:0000458	99.38	gold quality
epithelial cell of pancreas	CL:0000083	99.36	gold quality
monocyte	CL:0000576	99.36	gold quality
upper arm skin	UBERON:0004263	99.34	gold quality
leukocyte	CL:0000738	99.33	gold quality
mucosa of stomach	UBERON:0001199	99.33	gold quality
ectocervix	UBERON:0012249	99.32	gold quality
germinal epithelium of ovary	UBERON:0001304	99.30	gold quality
left uterine tube	UBERON:0001303	99.27	gold quality
left ovary	UBERON:0002119	99.27	gold quality
gall bladder	UBERON:0002110	99.26	gold quality
muscle layer of sigmoid colon	UBERON:0035805	99.26	gold quality
right lung	UBERON:0002167	99.25	gold quality
visceral pleura	UBERON:0002401	99.25	gold quality
left lobe of thyroid gland	UBERON:0001120	99.24	gold quality
right ovary	UBERON:0002118	99.24	gold quality
tibial nerve	UBERON:0001323	99.23	gold quality
epithelium of nasopharynx	UBERON:0001951	99.22	gold quality
thyroid gland	UBERON:0002046	99.22	gold quality
popliteal artery	UBERON:0002250	99.22	gold quality

Single-cell (SCXA)

Detected in 63 experiment(s), a significant marker in 25.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	7477.96
E-MTAB-10042	yes	6403.23
E-MTAB-10432	yes	6177.31
E-HCAD-4	yes	5569.10
E-GEOD-180759	yes	4655.46
E-MTAB-9906	yes	4241.89
E-HCAD-10	yes	4213.18
E-GEOD-139324	yes	3888.13
E-MTAB-6653	yes	3816.12
E-HCAD-15	yes	2926.50
E-MTAB-8142	yes	2763.50
E-CURD-122	yes	2527.42
E-MTAB-9067	yes	2338.25
E-CURD-88	yes	2239.79
E-MTAB-8207	yes	1985.71

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
IL1B	Activation
IL2RA	Activation
IL5	Activation
TNF	Repression

Upstream regulators (CollecTRI, top): AP1, CEBPA, CEBPG, E2F4, ESR1, EVX2, GATA2, GBX2, HBP1, IRF6, KDM5A, KLF4, NFIC, NFKB, STAT1, STAT3, TP53

miRNA regulators (miRDB)

110 targeting HMGB1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-589-3P	99.91	69.62	2088

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 83.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• ubiquitously expressed HMGB1 and HMGB2 have potential to cell- and promoter-specifically down- or up-regulate in vivo transcriptional activity of different members of the p53 family (PMID:11748232)
• Release of chromatin protein HMGB1 by necrotic cells triggers inflammation; hmgb1(-/-) necrotic cells have a greatly reduced ability to promote inflammation, which proves that the release of HMGB1 can signal the demise of a cell to its neighbours (PMID:12110890)
• HMGB1 is produced and stored intracellularly in the adenoid gland and contributes to the local antibacterial barrier defense system in the upper respiratory tract. (PMID:12149489)
• HMGB1 secretion from monocytes is induced by stimuli triggering lysosome exocytosis (PMID:12231511)
• pathogenetic role for HMGB-1 in synovitis (PMID:12384917)
• effects on human microvascular endothelial cells (PMID:12456506)
• REVIEW: role of extracellular and nuclear HMGB1 as an inflammation mediator (PMID:12488489)
• HMG1 may regulate the homeostasis of extracellular amyloid-beta peptides in Alzheimer’s disease. (PMID:12565837)
• HMGB1 leads to a different profile of gene expression, pattern of cytokine expression, and kinetics of p38 activation compared with LPS. (PMID:12620891)
• Stable antisense-HMG1 expression in melanoma cells led to the reduction of MIA promoter activity and protein expression. (PMID:12665595)
• Overexpression of HMGB1 is common in gastrointestinal stromal tumors and is related to the KIT mutation. (PMID:12727838)
• HMGB1 is abundantly expressed in human breast carcinoma. (PMID:12759333)
• Lipopolysaccharides (endotoxins) stimulate expression of this protein in skeletal muscle. (PMID:12785009)
• The acidic C-terminal domain and A-box of HMGB-1 regulates p53-mediated transcription. (PMID:12799451)
• Intracellular expression repressed HIV-1 gene expression in Hela cells and monocytic cells by repression of terminal repeat (LTR)-mediated transcription, but did not affect HIV replication in unstimulated Jurkat cells. (PMID:14517071)
• molecular characterization of the mechanism of HMGB1 transfer from the nucleus to secretory lysosomes (PMID:14532127)
• Amphoterin induction in prostatic stromal cells by androgen deprivation is associated with metastatic prostate cancer (PMID:14534709)
• interaction of estrogen receptor alpha and beta with HMGB requires the C-terminal extension (CTE) of the estrogen receptor alpha and beta DNA binding domain (PMID:14739282)
• Results suggest that HMGB1 is involved in chromatin structural modulation in global nuclear events through its interaction with a multiprotein complex in HeLa cells. (PMID:14999020)
• HMGB1 physically interacts with MutSalpha and is required at a step prior to the excision of mispaired nucleotide in mismatch repair. (PMID:15014079)
• results suggest that amphoterin is an autocrine/paracrine regulator of monocyte invasion through the endothelium. (PMID:15130941)
• The cytoplasmic and extracellular distribution of HMGB-1 in muscle tissue may indicate an important role of this proinflammatory molecule in the pathogenesis of polymyositis and dermatomyositis (PMID:15146429)
• HMGB1 is a proinflammatory mediator (review). (PMID:15162419)
• HMGB-1 with estrogen accelerates the cell cycle progression in tumor cell lines (PMID:15201494)
• The HMGB1 B box induces dendritic cell maturation and Th1 cell polarization. (PMID:15210788)
• in chlaymdia infected cells, HMGB1 is released by necrotic or permeabilized viable cells, but not apoptotic cells (PMID:15488733)
• HMGB1 in neutrophils is conformationally changed in the epitope or the peripheral structure of the epitope from the protein in lymphocytes (PMID:15496585)
• Amphoterin mRNA was expressed in three prostate cancer cell lines. (PMID:15666359)
• results identify extracellular HMGB1 as an activator of human tumour cell migration operating in concert with EGF (PMID:15733057)
• HMGB1/amphoterin induces growth inhibition and apoptosis in macrophages through RAGE intracellular signaling pathway (PMID:15743787)
• HMGB1 has the ability to recognize DNA interstrand cross-links (ICLs), can cooperate with replication protein A in doing so, and likely modulates ICL repair by the base excision repair machinery. (PMID:15766246)
• HMGB1 induced endothelial cell migration and sprouting (PMID:15793304)
• activated NK cells release HMGB1, which promotes inflammation and induces dendritic cell maturation, thus favoring the onset of the adaptive immune response (PMID:15802534)
• Serum HMG-1 increases in patients with trauma and is positively correlated with severity of trauma. (PMID:15877951)
• HMGB1 and RAGE are the first known autocrine loop proteins modulating the maturation of human plasmacytoid dendritic cells (PMID:15915542)
• A potential protein-folding pathway is proposed for the HMG box 1 domain of upstream binding factor based on the early stages of its pH 2.1 unfolded state characterized by multidimensional heteronuclear magnetic resonance spectroscopy. (PMID:15924431)
• HMGB1 secreted by maturing dendritic cells orchestrates the priming, activation, and Th1 polarization of T cells and upregulates dendritic cell surface markers and IL-12 production. (PMID:15944249)
• Data show that HMGB1 promotes RAG-mediated cleavage largely through the activity of box B, but optimal stimulation requires a functional A box tethered in the correct orientation. (PMID:15994314)
• HMGB1 is potentially involved in the regulation of lipogenic and cholesterogenic gene transcription (PMID:16040616)
• Data support the view that HMGB1 is secreted by immunostimulated enterocytes, which may exacerbate inflammation-induced epithelial hyperpermeability via an autocrine feedback loop. (PMID:16282196)

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
danio_rerio	hmgb1b	ENSDARG00000030479
danio_rerio	hmgb1a	ENSDARG00000099175
mus_musculus	Hmgb1	ENSMUSG00000066551
rattus_norvegicus	Hmgb1	ENSRNOG00000029813
rattus_norvegicus	Hmgb1l1	ENSRNOG00000030351
rattus_norvegicus	AABR07029613.1	ENSRNOG00000038478
rattus_norvegicus	Hmgb1l5	ENSRNOG00000051482
rattus_norvegicus	Hmgb1l2	ENSRNOG00000058908
rattus_norvegicus	Hmgb1l2	ENSRNOG00000067072
rattus_norvegicus	Hmgb1-ps34	ENSRNOG00000068306
rattus_norvegicus		ENSRNOG00000084828
caenorhabditis_elegans	hmg-3	WBGENE00001973
caenorhabditis_elegans		WBGENE00001974

Paralogs (20): HMGB3 (ENSG00000029993), HMG20B (ENSG00000064961), SP100 (ENSG00000067066), SMARCE1 (ENSG00000073584), SP140 (ENSG00000079263), TOX4 (ENSG00000092203), HMGXB4 (ENSG00000100281), TOX3 (ENSG00000103460), TFAM (ENSG00000108064), UBTF (ENSG00000108312), HMGB1P1 (ENSG00000124097), TOX2 (ENSG00000124191), SP110 (ENSG00000135899), HMG20A (ENSG00000140382), SSRP1 (ENSG00000149136), HMGB2 (ENSG00000164104), HMGB4 (ENSG00000176256), SP140L (ENSG00000185404), TOX (ENSG00000198846), UBTFL1 (ENSG00000255009)

Protein

Protein identifiers

High mobility group protein B1 — P09429 (reviewed: P09429)

Alternative names: High mobility group protein 1

All UniProt accessions (2): P09429, Q5T7C4

UniProt curated annotations — full annotation on UniProt →

Function. Multifunctional redox sensitive protein with various roles in different cellular compartments. In the nucleus is one of the major chromatin-associated non-histone proteins and acts as a DNA chaperone involved in replication, transcription, chromatin remodeling, V(D)J recombination, DNA repair and genome stability. Proposed to be an universal biosensor for nucleic acids. Promotes host inflammatory response to sterile and infectious signals and is involved in the coordination and integration of innate and adaptive immune responses. In the cytoplasm functions as a sensor and/or chaperone for immunogenic nucleic acids implicating the activation of TLR9-mediated immune responses, and mediates autophagy. Acts as a danger-associated molecular pattern (DAMP) molecule that amplifies immune responses during tissue injury. Released to the extracellular environment can bind DNA, nucleosomes, IL-1 beta, CXCL12, AGER isoform 2/sRAGE, lipopolysaccharide (LPS) and lipoteichoic acid (LTA), and activates cells through engagement of multiple surface receptors. In the extracellular compartment fully reduced HMGB1 (released by necrosis) acts as a chemokine, disulfide HMGB1 (actively secreted) as a cytokine, and sulfonyl HMGB1 (released from apoptotic cells) promotes immunological tolerance. Has proangiogdenic activity. May be involved in platelet activation. Binds to phosphatidylserine and phosphatidylethanolamide. Bound to RAGE mediates signaling for neuronal outgrowth. May play a role in accumulation of expanded polyglutamine (polyQ) proteins such as huntingtin (HTT) or TBP. Nuclear functions are attributed to fully reduced HGMB1. Associates with chromatin and binds DNA with a preference to non-canonical DNA structures such as single-stranded DNA, DNA-containing cruciforms or bent structures, supercoiled DNA and ZDNA. Can bent DNA and enhance DNA flexibility by looping thus providing a mechanism to promote activities on various gene promoters by enhancing transcription factor binding and/or bringing distant regulatory sequences into close proximity. May have an enhancing role in nucleotide excision repair (NER). However, effects in NER using in vitro systems have been reported conflictingly. May be involved in mismatch repair (MMR) and base excision repair (BER) pathways. May be involved in double strand break repair such as non-homologous end joining (NHEJ). Involved in V(D)J recombination by acting as a cofactor of the RAG complex: acts by stimulating cleavage and RAG protein binding at the 23 bp spacer of conserved recombination signal sequences (RSS). In vitro can displace histone H1 from highly bent DNA. Can restructure the canonical nucleosome leading to relaxation of structural constraints for transcription factor-binding. Enhances binding of sterol regulatory element-binding proteins (SREBPs) such as SREBF1 to their cognate DNA sequences and increases their transcriptional activities. Facilitates binding of TP53 to DNA. Proposed to be involved in mitochondrial quality control and autophagy in a transcription-dependent fashion implicating HSPB1; however, this function has been questioned. Can modulate the activity of the telomerase complex and may be involved in telomere maintenance. In the cytoplasm proposed to dissociate the BECN1:BCL2 complex via competitive interaction with BECN1 leading to autophagy activation. Involved in oxidative stress-mediated autophagy. Can protect BECN1 and ATG5 from calpain-mediated cleavage and thus proposed to control their proautophagic and proapoptotic functions and to regulate the extent and severity of inflammation-associated cellular injury. In myeloid cells has a protective role against endotoxemia and bacterial infection by promoting autophagy. Involved in endosomal translocation and activation of TLR9 in response to CpG-DNA in macrophages. In the extracellular compartment (following either active secretion or passive release) involved in regulation of the inflammatory response. 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; the CXCL12:HMGB1 complex triggers CXCR4 homodimerization. Induces the migration of monocyte-derived immature dendritic cells and seems to regulate adhesive and migratory functions of neutrophils implicating AGER/RAGE and ITGAM. Can bind to various types of DNA and RNA including microbial unmethylated CpG-DNA to enhance the innate immune response to nucleic acids. Proposed to act in promiscuous DNA/RNA sensing which cooperates with subsequent discriminative sensing by specific pattern recognition receptors. Promotes extracellular DNA-induced AIM2 inflammasome activation implicating AGER/RAGE. Disulfide HMGB1 binds to transmembrane receptors, such as AGER/RAGE, TLR2, TLR4 and probably TREM1, thus activating their signal transduction pathways. Mediates the release of cytokines/chemokines such as TNF, IL-1, IL-6, IL-8, CCL2, CCL3, CCL4 and CXCL10. Promotes secretion of interferon-gamma by macrophage-stimulated natural killer (NK) cells in concert with other cytokines like IL-2 or IL-12. TLR4 is proposed to be the primary receptor promoting macrophage activation and signaling through TLR4 seems to implicate LY96/MD-2. In bacterial LPS- or LTA-mediated inflammatory responses binds to the endotoxins and transfers them to CD14 for signaling to the respective TLR4:LY96 and TLR2 complexes. Contributes to tumor proliferation by association with ACER/RAGE. Can bind to IL1-beta and signals through the IL1R1:IL1RAP receptor complex. Binding to class A CpG activates cytokine production in plasmacytoid dendritic cells implicating TLR9, MYD88 and AGER/RAGE and can activate autoreactive B cells. Via HMGB1-containing chromatin immune complexes may also promote B cell responses to endogenous TLR9 ligands through a B-cell receptor (BCR)-dependent and ACER/RAGE-independent mechanism. Inhibits phagocytosis of apoptotic cells by macrophages; the function is dependent on poly-ADP-ribosylation and involves binding to phosphatidylserine on the cell surface of apoptotic cells. In adaptive immunity may be involved in enhancing immunity through activation of effector T cells and suppression of regulatory T (TReg) cells. In contrast, without implicating effector or regulatory T-cells, required for tumor infiltration and activation of T-cells expressing the lymphotoxin LTA:LTB heterotrimer thus promoting tumor malignant progression. Also reported to limit proliferation of T-cells. Released HMGB1:nucleosome complexes formed during apoptosis can signal through TLR2 to induce cytokine production. Involved in induction of immunological tolerance by apoptotic cells; its pro-inflammatory activities when released by apoptotic cells are neutralized by reactive oxygen species (ROS)-dependent oxidation specifically on Cys-106. During macrophage activation by activated lymphocyte-derived self apoptotic DNA (ALD-DNA) promotes recruitment of ALD-DNA to endosomes. (Microbial infection) Critical for entry of human coronaviruses SARS-CoV and SARS-CoV-2, as well as human coronavirus NL63/HCoV-NL63. Regulates the expression of the pro-viral genes ACE2 and CTSL through chromatin modulation. Required for SARS-CoV-2 ORF3A-induced reticulophagy which induces endoplasmic reticulum stress and inflammatory responses and facilitates viral infection. (Microbial infection) Associates with the influenza A viral protein NP in the nucleus of infected cells, promoting viral growth and enhancing the activity of the viral polymerase. (Microbial infection) Promotes Epstein-Barr virus (EBV) latent-to-lytic switch by sustaining the expression of the viral transcription factor BZLF1 that acts as a molecular switch to induce the transition from the latent to the lytic or productive phase of the virus cycle. Mechanistically, participates in EBV reactivation through the NLRP3 inflammasome. (Microbial infection) Facilitates dengue virus propagation via interaction with the untranslated regions of viral genome. In turn, this interaction with viral RNA may regulate secondary structure of dengue RNA thus facilitating its recognition by the replication complex.

Subunit / interactions. Interacts (fully reduced HMGB1) with CXCL12; probably in a 1:2 ratio involving two molecules of CXCL12, each interacting with one HMG box of HMGB1; inhibited by glycyrrhizin. Associates with the TLR4:LY96 receptor complex. Component of the RAG complex composed of core components RAG1 and RAG2, and associated component HMGB1 or HMGB2. Interacts (in cytoplasm upon starvation) with BECN1; inhibits the interaction of BECN1 and BCL2 leading to promotion of autophagy. Interacts with KPNA1; involved in nuclear import. Interacts with SREBF1, TLR2, TLR4, TLR9, PTPRZ1, APEX1, FEN1, POLB, TERT. Interacts with IL1B, AGER, MSH2, XPA, XPC, HNF1A, TP53. Interacts with CD24; the probable CD24:SIGLEC10 complex is proposed to inhibit HGMB1-mediated tissue damage immune response. Interacts with THBD; prevents HGMB1 interaction with ACER/RAGE and inhibits HGMB1 pro-inflammatory activity. Interacts with HAVCR2; impairs HMGB1 binding to B-DNA and likely HMGB1-mediated innate immune response. Interacts with XPO1; mediating nuclear export. Interacts with HTT (wild-type and mutant HTT with expanded polyglutamine repeat). Interacts with receptor RAGE/AGER. (Microbial infection) Interacts with adenovirus protein pVII; this interaction immobilizes HMGB1 on chromatin, thus preventing its release from cell and subsequent inflammation activation. (Microbial infection) Interacts with SARS-CoV-2 ORF3A protein; the interaction promotes association of HMGB1 with BECN1, promoting reticulophagy which induces endoplasmic reticulum stress and inflammatory responses and facilitates viral infection. (Microbial infection) Interacts with influenza A virus protein NP; this interaction promotes viral replication.

Subcellular location. Nucleus. Chromosome. Cytoplasm. Secreted. Cell membrane. Endosome. Endoplasmic reticulum-Golgi intermediate compartment Endoplasmic reticulum.

Tissue specificity. Ubiquitous. Expressed in platelets.

Post-translational modifications. Phosphorylated at serine residues. Phosphorylation in both NLS regions is required for cytoplasmic translocation followed by secretion. Acetylated on multiple sites upon stimulation with LPS. Acetylation on lysine residues in the nuclear localization signals (NLS 1 and NLS 2) leads to cytoplasmic localization and subsequent secretion. Acetylation on Lys-3 results in preferential binding to DNA ends and impairs DNA bending activity. Reduction/oxidation of cysteine residues Cys-23, Cys-45 and Cys-106 and a possible intramolecular disulfide bond involving Cys-23 and Cys-45 give rise to different redox forms with specific functional activities in various cellular compartments: 1- fully reduced HMGB1 (HMGB1C23hC45hC106h), 2- disulfide HMGB1 (HMGB1C23-C45C106h) and 3- sulfonyl HMGB1 (HMGB1C23soC45soC106so). Poly-ADP-ribosylated by PARP1 when secreted following stimulation with LPS. In vitro cleavage by CASP1 is liberating a HMG box 1-containing peptide which may mediate immunogenic activity; the peptide antagonizes apoptosis-induced immune tolerance. Can be proteolytically cleaved by a thrombin:thrombomodulin complex; reduces binding to heparin and pro-inflammatory activities. Forms covalent cross-links mediated by transglutaminase TGM2, between a glutamine and the epsilon-amino group of a lysine residue, forming homopolymers and heteropolymers.

Domain organisation. HMG box 2 mediates pro-inflammatory cytokine-stimulating activity and binding to TLR4. However, not involved in mediating immunogenic activity in the context of apoptosis-induced immune tolerance. The acidic C-terminal domain forms a flexible structure which can reversibly interact intramolecularily with the HMG boxes and modulate binding to DNA and other proteins.

Induction. (Microbial infection) Protein levels increase upon infection by human coronavirus SARS-CoV-2.

Miscellaneous. Proposed to contribute to the pathogenesis of various chronic inflammatory and autoimmune diseases, and cancer. High serum levels are found in several inflammatory events including sepsis, rheumatoid arthritis, artherosclerosis chronic kidney disease, systemic lupus erythematosus (SLE). Seems to be implicated in other diseases characterized by cell death and damage, including diabetes and Alzheimer’s disease. Its nucleosome-associated release during secondary necrosis may play a role in SLE. During chemotherapy can mediate regrowth and metastasis of remaining cells in a AGER/RAGE-dependent manner. Purified HMG box 1 acts as a specific antagonist to HGMB1 pro-inflammatory activities.

Similarity. Belongs to the HMGB family.

RefSeq proteins (7): NP_001300821, NP_001300822, NP_001350590, NP_001357268, NP_001357269, NP_001357270, NP_002119* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009071	HMG_box_dom	Domain
IPR017967	HMG_boxA_CS	Conserved_site
IPR036910	HMG_box_dom_sf	Homologous_superfamily
IPR050342	HMGB	Family

Pfam: PF00505, PF09011

UniProt features (85 total): modified residue 26, mutagenesis site 14, cross-link 8, region of interest 7, helix 7, strand 5, sequence variant 4, compositionally biased region 3, DNA-binding region 2, short sequence motif 2, site 2, sequence conflict 2, chain 1, binding site 1, disulfide bond 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
9CG9	ELECTRON MICROSCOPY	2.94
6CIK	X-RAY DIFFRACTION	3.15
6CG0	ELECTRON MICROSCOPY	3.17
6CIM	X-RAY DIFFRACTION	3.6
6OEM	ELECTRON MICROSCOPY	3.6
6OEO	ELECTRON MICROSCOPY	3.69
6CIJ	ELECTRON MICROSCOPY	3.9
6CIL	X-RAY DIFFRACTION	4.15
6OEN	ELECTRON MICROSCOPY	4.3
8I9M	ELECTRON MICROSCOPY	5.19
2LY4	SOLUTION NMR
2RTU	SOLUTION NMR
2YRQ	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P09429-F1	76.84	0.39

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 10–11 (cleavage; by thrombin:thrombomodulin); 67–68 (cleavage; by casp1)

Ligand- & substrate-binding residues (1): 1–10

Post-translational modifications (34): 3, 7, 8, 12, 23, 28, 29, 30, 35, 43, 45, 90, 100, 106, 127, 128, 141, 172, 173, 177 …

Disulfide bonds (1): 23–45

Mutagenesis-validated functional residues (14):

Position	Phenotype
35	greatly reduces phosphorylation, nuclear localization; when associated with a-39; a-42; a-46; a-53 and a-181.
35	cytoplasmic localization (phosphorylation mimicking); when associated with e-39; e-42; e-46; e-53 and e-181.
39	greatly reduces phosphorylation, nuclear localization; when associated with a-35; a-42; a-46; a-53 and a-181.
39	cytoplasmic localization (phosphorylation mimicking); when associated with e-35; e-42; e-46; e-53 and e-181.
42	greatly reduces phosphorylation, nuclear localization; when associated with a-35; a-39; a-46; a-53 and a-181.
42	cytoplasmic localization (phosphorylation mimicking); when associated with e-35; e-39; e-46; e-53 and e-181.
46	greatly reduces phosphorylation, nuclear localization; when associated with a-35; a-39; a-42; a-53 and a-181.
46	cytoplasmic localization (phosphorylation mimicking); when associated with e-35; e-39; e-42; e-53 and e-181.
53	greatly reduces phosphorylation, nuclear localization; when associated with a-35; a-39; a-42; a-46 and a-181.
53	cytoplasmic localization (phosphorylation mimicking); when associated with e-35; e-39; e-42; e-46 and e-181.
67	abolishes cleavage by casp1 and impairs ability to antagonize apoptosis-induced immune tolerance.
106	inhibits oxidation-dependent inactivation of immunostimmulatory activity in apoptotic cells.
181	greatly reduces phosphorylation, nuclear localization; when associated with a-35; a-39; a-42; a-46 and a-53.
181	cytoplasmic localization (phosphorylation mimicking); when associated with e-35; e-39; e-42; e-46 and e-53.

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-1236974	ER-Phagosome pathway
R-HSA-140342	Apoptosis induced DNA fragmentation
R-HSA-166058	MyD88:MAL(TIRAP) cascade initiated on plasma membrane
R-HSA-3000471	Scavenging by Class B Receptors
R-HSA-445989	TAK1-dependent IKK and NF-kappa-B activation
R-HSA-5602498	MyD88 deficiency (TLR2/4)
R-HSA-5603041	IRAK4 deficiency (TLR2/4)
R-HSA-5620971	Pyroptosis
R-HSA-5686938	Regulation of TLR by endogenous ligand
R-HSA-6798695	Neutrophil degranulation
R-HSA-879415	Advanced glycosylation endproduct receptor signaling
R-HSA-933542	TRAF6 mediated NF-kB activation

MSigDB gene sets: 810 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_CHROMOSOME_ORGANIZATION, REACTOME_APOPTOSIS_INDUCED_DNA_FRAGMENTATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, TAATAAT_MIR126, GOBP_DENDRITIC_CELL_DIFFERENTIATION, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_DENDRITIC_CELL_MIGRATION, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION

GO Biological Process (98): negative regulation of transcription by RNA polymerase II (GO:0000122), eye development (GO:0001654), myeloid dendritic cell activation (GO:0001773), endothelial cell proliferation (GO:0001935), activation of innate immune response (GO:0002218), plasmacytoid dendritic cell activation (GO:0002270), macrophage activation involved in immune response (GO:0002281), myeloid progenitor cell differentiation (GO:0002318), dendritic cell chemotaxis (GO:0002407), inflammatory response to antigenic stimulus (GO:0002437), regulation of tolerance induction (GO:0002643), regulation of T cell mediated immune response to tumor cell (GO:0002840), glycogen catabolic process (GO:0005980), DNA topological change (GO:0006265), base-excision repair (GO:0006284), double-strand break repair (GO:0006302), double-strand break repair via nonhomologous end joining (GO:0006303), DNA recombination (GO:0006310), chromatin remodeling (GO:0006338), transcription by RNA polymerase II (GO:0006366), autophagy (GO:0006914), inflammatory response (GO:0006954), positive regulation of cytosolic calcium ion concentration (GO:0007204), positive regulation of autophagy (GO:0010508), negative regulation of RNA polymerase II transcription preinitiation complex assembly (GO:0017055), myeloid cell differentiation (GO:0030099), lung development (GO:0030324), neuron projection development (GO:0031175), heterochromatin formation (GO:0031507), obsolete regulation of restriction endodeoxyribonuclease activity (GO:0032072), DNA geometric change (GO:0032392), positive regulation of mismatch repair (GO:0032425), negative regulation of type II interferon production (GO:0032689), positive regulation of interferon-alpha production (GO:0032727), positive regulation of interferon-beta production (GO:0032728), positive regulation of interleukin-1 beta production (GO:0032731), positive regulation of interleukin-1 production (GO:0032732), positive regulation of interleukin-10 production (GO:0032733), positive regulation of interleukin-12 production (GO:0032735), positive regulation of interleukin-6 production (GO:0032755)

GO Molecular Function (30): four-way junction DNA binding (GO:0000400), bubble DNA binding (GO:0000405), transcription cis-regulatory region binding (GO:0000976), lipopolysaccharide binding (GO:0001530), phosphatidylserine binding (GO:0001786), damaged DNA binding (GO:0003684), double-stranded DNA binding (GO:0003690), single-stranded DNA binding (GO:0003697), transcription coactivator activity (GO:0003713), transcription corepressor activity (GO:0003714), RNA binding (GO:0003723), double-stranded RNA binding (GO:0003725), single-stranded RNA binding (GO:0003727), cytokine activity (GO:0005125), integrin binding (GO:0005178), DNA binding, bending (GO:0008301), calcium-dependent protein kinase regulator activity (GO:0010858), lyase activity (GO:0016829), C-X-C chemokine binding (GO:0019958), protein kinase activator activity (GO:0030295), chemoattractant activity (GO:0042056), receptor ligand activity (GO:0048018), RAGE receptor binding (GO:0050786), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), DNA polymerase binding (GO:0070182), supercoiled DNA binding (GO:0097100), DNA-binding transcription factor binding (GO:0140297), DNA binding (GO:0003677), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (19): condensed chromosome (GO:0000793), extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), nucleus (GO:0005634), nucleoplasm (GO:0005654), early endosome (GO:0005769), endoplasmic reticulum (GO:0005783), endoplasmic reticulum-Golgi intermediate compartment (GO:0005793), cell surface (GO:0009986), transcription repressor complex (GO:0017053), secretory granule lumen (GO:0034774), alphav-beta3 integrin-HMGB1 complex (GO:0035868), neuron projection (GO:0043005), ficolin-1-rich granule lumen (GO:1904813), chromosome (GO:0005694), cytoplasm (GO:0005737), endosome (GO:0005768), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-17 pathways:

Category	Pathways
Diseases associated with the TLR signaling cascade	2
Innate Immune System	2
Antigen processing-Cross presentation	1
Apoptotic execution phase	1
Toll Like Receptor 4 (TLR4) Cascade	1
Toll Like Receptor TLR1:TLR2 Cascade	1
Toll Like Receptor TLR6:TLR2 Cascade	1
Binding and Uptake of Ligands by Scavenger Receptors	1
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	1
Toll Like Receptor 3 (TLR3) Cascade	1
Interleukin-1 signaling	1
TRIF (TICAM1)-mediated TLR4 signaling	1
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	1
MyD88 cascade initiated on plasma membrane	1
Regulated Necrosis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
DNA binding	4
intracellular membrane-bounded organelle	3
negative regulation of DNA-templated transcription	2
immune response	2
DNA metabolic process	2
DNA repair	2
DNA secondary structure binding	2
transcription coregulator activity	2
RNA binding	2
protein kinase regulator activity	2
cytoplasm	2
endomembrane system	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
sensory organ development	1
visual system development	1
myeloid leukocyte activation	1
epithelial cell proliferation	1
activation of immune response	1
positive regulation of innate immune response	1
leukocyte activation	1
myeloid cell activation involved in immune response	1
leukocyte activation involved in immune response	1
macrophage activation	1
hematopoietic progenitor cell differentiation	1
leukocyte chemotaxis	1
dendritic cell migration	1
inflammatory response	1
tolerance induction	1
regulation of immune system process	1
T cell mediated immune response to tumor cell	1
regulation of T cell mediated immunity	1
regulation of immune response to tumor cell	1
glycogen metabolic process	1
glucan catabolic process	1
DNA conformation change	1
double-strand break repair	1
chromatin organization	1
DNA-templated transcription	1

Protein interactions and networks

STRING

4488 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HMGB1	TLR4	O00206	999
HMGB1	AGER	Q15109	999
HMGB1	TLR9	Q9NR96	997
HMGB1	TLR2	O60603	996
HMGB1	HAVCR2	Q8TDQ0	991
HMGB1	CD24	P25063	991
HMGB1	BECN1	Q14457	988
HMGB1	CXCL12	P48061	979
HMGB1	SIGLEC10	Q96LC7	965
HMGB1	TREM1	Q9NP99	959
HMGB1	IL1B	P01584	959
HMGB1	TLR3	O15455	952
HMGB1	SDC1	P18827	921
HMGB1	LY96	Q9Y6Y9	917
HMGB1	CXCR4	P30991	906

IntAct

221 interactions, top by confidence:

A	B	Type	Score
HMGB1	TP53	psi-mi:“MI:0407”(direct interaction)	0.740
HMGB1	KRT7	psi-mi:“MI:0915”(physical association)	0.740
HMGB1	KRT7	psi-mi:“MI:0403”(colocalization)	0.740
HMGB1	TP53	psi-mi:“MI:0915”(physical association)	0.740
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
HMGB1	RSF1	psi-mi:“MI:0915”(physical association)	0.670
HMGB1	SP100	psi-mi:“MI:0914”(association)	0.670
HMGB1	SP100	psi-mi:“MI:0915”(physical association)	0.670
HMGB1	HNRNPU	psi-mi:“MI:0915”(physical association)	0.610
HMGB1	SRSF3	psi-mi:“MI:0915”(physical association)	0.610
TLR4	HMGB1	psi-mi:“MI:0915”(physical association)	0.600
HMGB1	TLR4	psi-mi:“MI:2364”(proximity)	0.600
TLR4	HMGB1	psi-mi:“MI:0914”(association)	0.600
AGTRAP	HMGB1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (763): HMGB1 (Affinity Capture-MS), AGTRAP (Two-hybrid), HMGB1 (Affinity Capture-MS), HMGB1 (Co-fractionation), HMGB1 (Co-fractionation), HMGB1 (Co-fractionation), HMGB1 (Co-fractionation), HMGB1 (Co-fractionation), HMGB1 (Co-fractionation), HMGB1 (Co-fractionation), KPNA6 (Co-fractionation), HMGB1 (Affinity Capture-MS), HMGB1 (Affinity Capture-MS), HMGB1 (Proximity Label-MS), HMGB1 (Affinity Capture-MS)

ESM2 similar proteins: A9RA84, B0CM99, B1MTB0, B2RPK0, O15347, O54879, P07156, P07746, P09429, P0CO24, P0CO25, P10103, P11873, P12682, P17741, P25979, P25980, P26583, P26584, P26586, P30681, P40618, P40620, P40621, P40622, P40623, P40625, P40626, P40632, P40644, P40673, P52925, P63158, P63159, P87057, Q05783, Q06943, Q07053, Q08IE6, Q09390

Diamond homologs: A9RA84, B0CM99, B1MTB0, B2RPK0, O01683, O04235, O15347, O15405, O49595, O49596, O49597, O54879, O64702, O94842, O94900, P07156, P07746, P09429, P0CO24, P0CO25, P10103, P11632, P11633, P11873, P12682, P17741, P23497, P26583, P26584, P26585, P26586, P27347, P30681, P40618, P40619, P40620, P40621, P40622, P40623, P40632

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
HMGB1	“up-regulates quantity by expression”	IL2RA	“transcriptional regulation”
HMGB1	“up-regulates activity”	TLR4	binding
CAMK4	“up-regulates activity”	HMGB1	phosphorylation
HMGB1	“up-regulates activity”	HOXD9	binding
LY96	“up-regulates activity”	HMGB1	binding
HMGB1	“up-regulates activity”	AGER	binding
HMGB1	“up-regulates activity”	HOXB1	binding
HMGB1	“up-regulates activity”	HOXB3	binding
HMGB1	“up-regulates activity”	HOXC6	binding
HMGB1	“up-regulates activity”	HOXD3	binding
HMGB1	“up-regulates activity”	HOXD10	binding
HMGB1	“up-regulates activity”	HOXD11	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 148 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of interferon-beta production	5	14.7×	4e-03
cellular response to amyloid-beta	5	14.7×	4e-03
cellular response to UV	5	11.1×	8e-03
obsolete positive regulation of NF-kappaB transcription factor activity	7	10.8×	2e-03
response to ethanol	7	7.7×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

41 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	5
Uncertain significance	11
Likely benign	5
Benign	6

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
1810205	NM_002128.7(HMGB1):c.556_559del (p.Glu186fs)	Pathogenic
1810206	NM_002128.7(HMGB1):c.551_554del (p.Lys184fs)	Pathogenic
3244203	NC_000013.10:g.(?30999468)(31204468_?)del	Pathogenic
3708238	NM_002128.7(HMGB1):c.220_221del (p.Glu74fs)	Pathogenic
1275810	NM_002128.7(HMGB1):c.406_407del (p.Thr136fs)	Likely pathogenic
2664997	NM_002128.7(HMGB1):c.47_48del (p.Tyr16fs)	Likely pathogenic
3377228	NM_002128.7(HMGB1):c.466G>T (p.Glu156Ter)	Likely pathogenic
4279330	GRCh37/hg19 13q12.3(chr13:31012732-31074339)x1	Likely pathogenic
443537	GRCh37/hg19 13q12.3(chr13:30841652-31177774)x1	Likely pathogenic

SpliceAI

2288 predictions. Top by Δscore:

Variant	Effect	Δscore
13:30461529:ATATC:A	acceptor_gain	1.0000
13:30461530:TATC:T	acceptor_gain	1.0000
13:30461531:ATC:A	acceptor_gain	1.0000
13:30461532:TC:T	acceptor_gain	1.0000
13:30461532:TCC:T	acceptor_loss	1.0000
13:30461533:CC:C	acceptor_gain	1.0000
13:30461534:C:CA	acceptor_loss	1.0000
13:30461534:C:CC	acceptor_gain	1.0000
13:30461534:C:T	acceptor_gain	1.0000
13:30461538:C:CT	acceptor_gain	1.0000
13:30461538:C:T	acceptor_gain	1.0000
13:30461539:A:T	acceptor_gain	1.0000
13:30461543:C:CT	acceptor_gain	1.0000
13:30461544:A:T	acceptor_gain	1.0000
13:30461553:A:AC	acceptor_gain	1.0000
13:30461553:A:C	acceptor_gain	1.0000
13:30461559:CAG:C	acceptor_gain	1.0000
13:30461560:A:T	acceptor_gain	1.0000
13:30461561:G:C	acceptor_gain	1.0000
13:30461561:G:GC	acceptor_gain	1.0000
13:30462535:TACCT:T	donor_loss	1.0000
13:30462536:A:AC	donor_gain	1.0000
13:30462536:AC:A	donor_gain	1.0000
13:30462537:C:CG	donor_gain	1.0000
13:30462537:CC:C	donor_gain	1.0000
13:30462537:CCT:C	donor_gain	1.0000
13:30462537:CCTT:C	donor_gain	1.0000
13:30462537:CCTTT:C	donor_gain	1.0000
13:30462708:CCGAA:C	acceptor_gain	1.0000
13:30462709:CGAA:C	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000029065 (13:30548490 C>G), RS1000034433 (13:30538192 G>A), RS1000054575 (13:30458869 T>C), RS1000081160 (13:30480607 C>T), RS1000082540 (13:30522533 G>A,T), RS1000106236 (13:30599093 T>C), RS1000163715 (13:30531686 G>A), RS1000175895 (13:30564973 C>A), RS1000179843 (13:30462908 A>C,G), RS1000192777 (13:30500448 C>T), RS1000210453 (13:30525683 G>A), RS1000218189 (13:30531444 C>A,T), RS1000236286 (13:30559318 A>G), RS1000243198 (13:30515467 T>C), RS1000253404 (13:30578534 T>C,G)

Disease associations

OMIM: gene MIM:163905 | disease phenotypes: MIM:609945

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Autosomal dominant
intellectual disability	Limited	Autosomal dominant

Mondo (3): brachyphalangy, polydactyly, and tibial aplasia/hypoplasia (MONDO:0012374), neurodevelopmental disorder (MONDO:0700092), intellectual disability (MONDO:0001071)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST000890_2	Hippocampal volume	7.000000e-06
GCST004162_9	Carotid plaque burden	8.000000e-06
GCST004267_6	Blood osmolality (transformed sodium)	5.000000e-06
GCST004602_166	Mean corpuscular volume	6.000000e-10
GCST004602_167	Mean corpuscular volume	8.000000e-12
GCST004630_190	Mean corpuscular hemoglobin	2.000000e-10
GCST008971_136	Urate levels	2.000000e-08
GCST008972_208	Urate levels	2.000000e-08
GCST009379_356	Type 2 diabetes	1.000000e-08
GCST010173_137	Triglyceride levels	3.000000e-09
GCST010241_241	Apolipoprotein A1 levels	3.000000e-09
GCST010244_294	Triglyceride levels	3.000000e-12
GCST010988_463	Adult body size	4.000000e-09
GCST011771_1	Rapid response to perioperative phenylephrine (change in mean arterial pressure)	2.000000e-08
GCST90002381_65	Eosinophil count	3.000000e-12
GCST90002381_66	Eosinophil count	1.000000e-16
GCST90002382_201	Eosinophil percentage of white cells	2.000000e-12
GCST90002382_202	Eosinophil percentage of white cells	9.000000e-15
GCST90002390_185	Mean corpuscular hemoglobin	8.000000e-13
GCST90002390_186	Mean corpuscular hemoglobin	3.000000e-10
GCST90002392_406	Mean corpuscular volume	6.000000e-15
GCST90002392_407	Mean corpuscular volume	3.000000e-11
GCST90002396_546	Mean reticulocyte volume	3.000000e-10
GCST90002403_468	Red blood cell count	2.000000e-10

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0005035	hippocampal volume
EFO:0006501	carotid plaque build
EFO:0004527	mean corpuscular hemoglobin
EFO:0004531	urate measurement
EFO:0004530	triglyceride measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0006943	blood pressure change measurement
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0010701	mean reticulocyte volume
EFO:0004305	erythrocyte count

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
C537100	Brachyphalangy, polydactyly, and tibial aplasia-hypoplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2311236 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

7 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,934,210 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL25	ASPIRIN	4	694,602
CHEMBL34259	METHOTREXATE	4	398,396
CHEMBL424	SALICYLIC ACID	4	669,423
CHEMBL898	DIFLUNISAL	4	54,786
CHEMBL226335	RUTIN	3	57,988
CHEMBL250450	ISOQUERCETIN	2	1,626
CHEMBL441687	GLYCYRRHIZIN	2	57,389

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1045411	HMGB1		0.00	0
rs1412125	HMGB1		0.00	0
rs2249825	HMGB1		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — High Mobility Group (HMG) proteins

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
3-AESA	Inhibition	8.83	pKd
methotrexate	Inhibition	7.62	pKd

ChEMBL bioactivities

26 potent at pChembl≥5 of 34 total, top 22 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.83	Kd	1.48	nM	CHEMBL4129393
7.62	Kd	24	nM	METHOTREXATE
7.30	Kd	50.34	nM	CHEMBL5653589
7.30	ED50	50.34	nM	CHEMBL5653589
7.00	Kd	100	nM	ISOQUERCETIN
6.92	Kd	120	nM	CALYCOSIN
6.73	Kd	187	nM	CHEMBL6133033
6.58	Kd	260	nM	RUTIN
6.30	Kd	500	nM	METHOTREXATE
6.10	Kd	800	nM	CHEMBL4867183
6.10	Kd	800	nM	CHEMBL4875121
6.05	Kd	900	nM	CHEMBL113835
6.00	Kd	1000	nM	SALICYLIC ACID
6.00	Kd	1000	nM	ASPIRIN
5.92	Kd	1200	nM	CHEMBL114721
5.72	Kd	1900	nM	CHEMBL4858278
5.52	Kd	3008	nM	CHEMBL3752910
5.52	ED50	3008	nM	CHEMBL3752910
5.35	Kd	4500	nM	CHEMBL1615534
5.24	Kd	5800	nM	CHEMBL4860199
5.07	Kd	8600	nM	CHEMBL4858896
5.00	Kd	9900	nM	CHEMBL4850898

PubChem BioAssay actives

15 with measured affinity, of 53 total; 11 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-(2-aminoethyl)-2-hydroxybenzoic acid	1494167: Binding affinity to recombinant HMGB1 box A (unknown origin)	kd	0.0015	uM
Methotrexate	1494165: Binding affinity to N-terminal 6His-tagged HMGB1 Bj region (88 to 181 residues) (unknown origin) expressed in Escherichia coli JM109 by SPR assay	kd	0.0240	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148518: Binding affinity to human HMGB1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0503	uM
(4S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(2-aminoacetyl)amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(1S)-1-carboxy-2-(1H-imidazol-5-yl)ethyl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-oxopentanoic acid	1773955: Binding affinity to 6His-tagged HMGB1 (unknown origin) incubated for 15 mins by MST analysis	kd	0.8000	uM
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(2-aminoacetyl)amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-(1H-imidazol-5-yl)propanoic acid	1773955: Binding affinity to 6His-tagged HMGB1 (unknown origin) incubated for 15 mins by MST analysis	kd	0.8000	uM
Salicylic Acid	1494167: Binding affinity to recombinant HMGB1 box A (unknown origin)	kd	1.0000	uM
(4S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(2-aminoacetyl)amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(1S)-1-carboxy-2-(1H-imidazol-5-yl)ethyl]amino]-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-oxopentanoic acid	1773955: Binding affinity to 6His-tagged HMGB1 (unknown origin) incubated for 15 mins by MST analysis	kd	1.9000	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148518: Binding affinity to human HMGB1 incubated for 45 mins by Kinobead based pull down assay	kd	3.0084	uM
(4S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(2-aminoacetyl)amino]propanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(1S)-1-carboxy-2-(1H-imidazol-5-yl)ethyl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-oxopentanoic acid	1773955: Binding affinity to 6His-tagged HMGB1 (unknown origin) incubated for 15 mins by MST analysis	kd	5.8000	uM
(4S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-aminopropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(1S)-1-carboxy-2-(1H-imidazol-5-yl)ethyl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-oxopentanoic acid	1773955: Binding affinity to 6His-tagged HMGB1 (unknown origin) incubated for 15 mins by MST analysis	kd	8.6000	uM
(4S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(2-aminoacetyl)amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]propanoyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(1S)-1-carboxy-2-(1H-imidazol-5-yl)ethyl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-oxopentanoic acid	1773955: Binding affinity to 6His-tagged HMGB1 (unknown origin) incubated for 15 mins by MST analysis	kd	9.9000	uM

CTD chemical–gene interactions

178 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Lipopolysaccharides	affects cotreatment, decreases reaction, increases expression, increases reaction, increases secretion (+1 more)	9
bisphenol A	affects expression, decreases expression, increases expression	3
Resveratrol	affects cotreatment, increases expression, decreases reaction, increases acetylation, increases reaction	3
Acetylcysteine	decreases reaction, increases expression, increases reaction, increases secretion	3
Ethanol	decreases reaction, increases secretion, increases expression, affects reaction	3
Hydrogen Peroxide	affects expression, affects localization, affects binding, increases reaction	3
Asbestos, Crocidolite	increases expression, decreases reaction, increases reaction, affects localization, increases secretion	3
Particulate Matter	decreases expression, increases abundance, increases expression	3
1-(3,4-dihydroxyphenyl)-3-(2-methoxyphenyl)prop-2-en-1-one	decreases reaction, increases reaction, affects binding	2
sodium arsenite	affects binding, increases reaction, decreases expression	2
acteoside	increases expression, increases activity, decreases expression, decreases reaction	2
SRT1720	decreases reaction, increases acetylation, increases expression, increases secretion	2
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	affects binding, increases reaction, affects localization, increases expression, decreases reaction (+1 more)	2
Sorafenib	decreases reaction, increases expression	2
Decitabine	affects expression, decreases expression, affects reaction	2
Arsenic Trioxide	increases expression, increases secretion, decreases response to substance	2
Caffeine	decreases expression, decreases phosphorylation	2
Cisplatin	affects expression, increases secretion, decreases reaction	2
Estradiol	decreases expression, increases expression	2
Gallic Acid	decreases reaction, increases secretion, increases expression, affects reaction	2
Glucose	affects binding, decreases reaction, increases reaction, increases expression, increases secretion (+1 more)	2
Plant Extracts	decreases expression, affects cotreatment, increases expression	2
Valproic Acid	decreases expression, decreases methylation	2
tert-Butylhydroperoxide	affects binding, decreases reaction, increases reaction, increases expression	2
aristolochic acid I	decreases expression	1
corynoxine B	affects binding, affects reaction, decreases reaction, increases reaction	1
TAK-243	affects sumoylation	1
EB-47	decreases reaction, increases secretion	1
dicrotophos	decreases expression	1
2-anisidine	increases expression	1

ChEMBL screening assays

36 unique, capped per target: 36 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2320415	Binding	Binding affinity to HMGB1 (unknown origin)	Synthesis, biological evaluation, and molecular modeling of glycyrrhizin derivatives as potent high-mobility group box-1 inhibitors with anti-heart-failure activity in vivo. — J Med Chem

Cellosaurus cell lines

10 cell lines: 7 cancer cell line, 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A2S9	SEES3-1V human HMGB1, clone1	Embryonic stem cell	Male
CVCL_A2T0	SEES3-1V human HMGB1, clone2	Embryonic stem cell	Male
CVCL_A2T1	SEES3-1V human HMGB1, clone3	Embryonic stem cell	Male
CVCL_A8BE	THP1-HMGB1-Lucia	Cancer cell line	Male
CVCL_AW25	K562 eGFP-HMGB1	Cancer cell line	Female
CVCL_B1TQ	Abcam HeLa HMGB1 KO	Cancer cell line	Female
CVCL_E0EB	Ubigene HeLa HMGB1 KO	Cancer cell line	Female
CVCL_E0XI	Ubigene LS174T HMGB1 KO	Cancer cell line	Female
CVCL_E8F2	HT1080-HMGB1-Lucia	Cancer cell line	Male
CVCL_KT65	HeLa SilenciX HMGB1	Cancer cell line	Female

Clinical trials (associated diseases)

299 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays