| Identification |
|---|
| HMDB Protein ID
| HMDBP13739 |
| Secondary Accession Numbers
| None |
| Name
| High mobility group protein B1 |
| Synonyms
|
- High mobility group protein 1
- HMG-1
|
| Gene Name
| HMGB1 |
| Protein Type
| Unknown |
| Biological Properties |
|---|
| General Function
| Not Available |
| Specific 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 sensor and/or chaperone for immunogenic nucleic acids implicating the activation of TLR9-mediated immune responses, and mediates autophagy. Acts as 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 (PubMed:23519706, PubMed:23446148, PubMed:23994764, PubMed:25048472). Has proangiogenic 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 (By similarity).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 be involved in nucleotide excision repair (NER), mismatch repair (MMR) and base excision repair (BER) pathways, and 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) (By similarity). 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 (PubMed:22941653). 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. May be involved in mitochondrial quality control and autophagy in a transcription-dependent fashion implicating HSPB1. Can modulate the activity of the telomerase complex and may be involved in telomere maintenance (By similarity).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 (By similarity).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 (By similarity). Induces the migration of monocyte-derived immature dendritic cells and seems to regulate adhesive and migratory functions of neutrophils implicating AGER/RAGE and ITGAM (PubMed:16966386). 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 (By similarity). Disulfide HMGB1 binds to transmembrane receptors, such as AGER/RAGE, TLR2, TLR4 and probably TREM1, thus activating their signal transduction pathways (PubMed:17417641). 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 (By similarity). Binding to class A CpG activates cytokine production in plasmacytoid dendritic cells implicating TLR9, MYD88 and AGER/RAGE and can activate autoreactive B cells (PubMed:17417641). 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 (PubMed:20014975). 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 (By similarity). |
| Pathways
|
- Autophagy - animal
- Base excision repair
- Necroptosis
- Neutrophil extracellular trap formation
|
| Reactions
| Not Available |
| GO Classification
|
| Biological Process |
| elevation of cytosolic calcium ion concentration |
| positive regulation of apoptotic process |
| positive regulation of interleukin-10 production |
| negative regulation of interferon-gamma production |
| positive regulation of interleukin-8 production |
| B cell proliferation involved in immune response |
| dendritic cell chemotaxis |
| DNA geometric change |
| myeloid dendritic cell activation |
| negative regulation of apoptotic cell clearance |
| negative regulation of blood vessel endothelial cell migration |
| negative regulation of CD4-positive, alpha-beta T cell differentiation |
| negative regulation of RNA polymerase II transcription preinitiation complex assembly |
| neutrophil clearance |
| plasmacytoid dendritic cell activation |
| positive regulation of autophagy |
| positive regulation of chemokine (C-X-C motif) ligand 2 production |
| positive regulation of dendritic cell differentiation |
| positive regulation of DNA ligation |
| DNA repair |
| positive regulation of interleukin-1 production |
| positive regulation of mismatch repair |
| positive regulation of toll-like receptor 9 signaling pathway |
| regulation of restriction endodeoxyribonuclease activity |
| regulation of T cell mediated immune response to tumor cell |
| regulation of tolerance induction |
| T-helper 1 cell activation |
| V(D)J recombination |
| activation of innate immune response |
| positive regulation of interleukin-12 production |
| positive regulation of DNA binding |
| positive regulation of cysteine-type endopeptidase activity involved in apoptotic process |
| positive regulation of vascular endothelial cell proliferation |
| positive regulation of blood vessel endothelial cell migration |
| positive regulation of ERK1 and ERK2 cascade |
| chromatin remodeling |
| regulation of transcription from RNA polymerase II promoter |
| positive regulation of interferon-alpha production |
| DNA topological change |
| positive regulation of monocyte chemotaxis |
| innate immune response |
| positive regulation of transcription from RNA polymerase II promoter |
| inflammatory response to antigenic stimulus |
| positive regulation of tumor necrosis factor production |
| positive regulation of JNK cascade |
| positive regulation of interleukin-6 production |
| DNA recombination |
| nucleosome assembly |
| apoptotic cell clearance |
| positive regulation of activated T cell proliferation |
| toll-like receptor 9 signaling pathway |
| T-helper 1 cell differentiation |
| chromatin silencing |
| autophagy |
| Cellular Component |
| cell surface |
| condensed chromosome |
| alphav-beta3 integrin-HMGB1 complex |
| nucleus |
| transcriptional repressor complex |
| endoplasmic reticulum-Golgi intermediate compartment |
| chromatin |
| extracellular space |
| endosome |
| Molecular Function |
| lipopolysaccharide binding |
| C-X-C chemokine binding |
| DNA binding, bending |
| DNA polymerase binding |
| four-way junction DNA binding |
| non-sequence-specific DNA binding, bending |
| RAGE receptor binding |
| repressing transcription factor binding |
| supercoiled DNA binding |
| unmethylated CpG binding |
| chemoattractant activity |
| bubble DNA binding |
| single-stranded DNA binding |
| integrin binding |
| phosphatidylserine binding |
| double-stranded DNA binding |
| transcription coactivator activity |
| damaged DNA binding |
| histone binding |
| lyase activity |
| transcription regulatory region sequence-specific DNA binding |
|
| Cellular Location
|
Not Available
|
| Gene Properties |
|---|
| Chromosome Location
| Not Available |
| Locus
| Not Available |
| SNPs
| Not Available |
| Gene Sequence
|
Not Available
|
| Protein Properties |
|---|
| Number of Residues
| 215 |
| Molecular Weight
| 24907.61 |
| Theoretical pI
| 5.739 |
| Pfam Domain Function
|
|
| Signals
|
Not Available
|
|
Transmembrane Regions
|
Not Available
|
| Protein Sequence
|
Not Available
|
| External Links |
|---|
| GenBank ID Protein
| Not Available |
| UniProtKB/Swiss-Prot ID
| P10103 |
| UniProtKB/Swiss-Prot Entry Name
| HMGB1_BOVIN |
| PDB IDs
|
Not Available |
| GenBank Gene ID
| Not Available |
| GeneCard ID
| Not Available |
| GenAtlas ID
| Not Available |
| HGNC ID
| Not Available |
| References |
|---|
| General References
| - Harhay GP, Sonstegard TS, Keele JW, Heaton MP, Clawson ML, Snelling WM, Wiedmann RT, Van Tassell CP, Smith TP: Characterization of 954 bovine full-CDS cDNA sequences. BMC Genomics. 2005 Nov 23;6:166. doi: 10.1186/1471-2164-6-166. [PubMed:16305752 ]
- Kaplan DJ, Duncan CH: Full length cDNA sequence for bovine high mobility group 1 (HMG1) protein. Nucleic Acids Res. 1988 Nov 11;16(21):10375. doi: 10.1093/nar/16.21.10375. [PubMed:3194213 ]
- Pentecost B, Dixon GH: Isolation and partial sequence of bovine cDNA clones for the high-mobility-group protein (HMG-1). Biosci Rep. 1984 Jan;4(1):49-57. doi: 10.1007/BF01120823. [PubMed:6141822 ]
- Walker JM, Gooderham K, Hastings JR, Mayes E, Johns EW: The primary structures of non-histone chromosomal proteins HMG 1 and 2. FEBS Lett. 1980 Dec 29;122(2):264-70. doi: 10.1016/0014-5793(80)80453-4. [PubMed:7202717 ]
- Christen T, Bischoff M, Hobi R, Kuenzle CC: High mobility group proteins 1 and 2 bind preferentially to brominated poly(dG-dC).poly(dG-dC) in the Z-DNA conformation but not to other types of Z-DNA. FEBS Lett. 1990 Jul 2;267(1):139-41. doi: 10.1016/0014-5793(90)80308-6. [PubMed:2365081 ]
- Itkes AV, Glotov BO, Nikolaev LG, Severin ES: Clusters of nonhistone chromosomal protein HMG1 molecules in intact chromatin. FEBS Lett. 1980 Aug 25;118(1):63-6. doi: 10.1016/0014-5793(80)81219-1. [PubMed:7409193 ]
- Bonaldi T, Talamo F, Scaffidi P, Ferrera D, Porto A, Bachi A, Rubartelli A, Agresti A, Bianchi ME: Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J. 2003 Oct 15;22(20):5551-60. doi: 10.1093/emboj/cdg516. [PubMed:14532127 ]
- Yang D, Chen Q, Yang H, Tracey KJ, Bustin M, Oppenheim JJ: High mobility group box-1 protein induces the migration and activation of human dendritic cells and acts as an alarmin. J Leukoc Biol. 2007 Jan;81(1):59-66. doi: 10.1189/jlb.0306180. Epub 2006 Sep 11. [PubMed:16966386 ]
- Tian J, Avalos AM, Mao SY, Chen B, Senthil K, Wu H, Parroche P, Drabic S, Golenbock D, Sirois C, Hua J, An LL, Audoly L, La Rosa G, Bierhaus A, Naworth P, Marshak-Rothstein A, Crow MK, Fitzgerald KA, Latz E, Kiener PA, Coyle AJ: Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol. 2007 May;8(5):487-96. doi: 10.1038/ni1457. Epub 2007 Apr 8. [PubMed:17417641 ]
- Avalos AM, Kiefer K, Tian J, Christensen S, Shlomchik M, Coyle AJ, Marshak-Rothstein A: RAGE-independent autoreactive B cell activation in response to chromatin and HMGB1/DNA immune complexes. Autoimmunity. 2010 Feb;43(1):103-10. doi: 10.3109/08916930903384591. [PubMed:20014975 ]
- Ito T, Kawahara K, Okamoto K, Yamada S, Yasuda M, Imaizumi H, Nawa Y, Meng X, Shrestha B, Hashiguchi T, Maruyama I: Proteolytic cleavage of high mobility group box 1 protein by thrombin-thrombomodulin complexes. Arterioscler Thromb Vasc Biol. 2008 Oct;28(10):1825-30. doi: 10.1161/ATVBAHA.107.150631. Epub 2008 Jul 3. [PubMed:18599803 ]
- Joshi SR, Sarpong YC, Peterson RC, Scovell WM: Nucleosome dynamics: HMGB1 relaxes canonical nucleosome structure to facilitate estrogen receptor binding. Nucleic Acids Res. 2012 Nov 1;40(20):10161-71. doi: 10.1093/nar/gks815. Epub 2012 Aug 31. [PubMed:22941653 ]
- Yang H, Antoine DJ, Andersson U, Tracey KJ: The many faces of HMGB1: molecular structure-functional activity in inflammation, apoptosis, and chemotaxis. J Leukoc Biol. 2013 Jun;93(6):865-73. doi: 10.1189/jlb.1212662. Epub 2013 Feb 27. [PubMed:23446148 ]
- Li G, Tang D, Lotze MT: Menage a Trois in stress: DAMPs, redox and autophagy. Semin Cancer Biol. 2013 Oct;23(5):380-90. doi: 10.1016/j.semcancer.2013.08.002. Epub 2013 Aug 28. [PubMed:23994764 ]
- Lee SA, Kwak MS, Kim S, Shin JS: The role of high mobility group box 1 in innate immunity. Yonsei Med J. 2014 Sep;55(5):1165-76. doi: 10.3349/ymj.2014.55.5.1165. [PubMed:25048472 ]
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