HMGB1

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High mobility group box 1

PDB rendering based on 1aab.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
SymbolsHMGB1; HMG1; HMG3; SBP-1
External IDsOMIM: 163905 MGI: 96113 HomoloGene: 110676 GeneCards: HMGB1 Gene
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez314615289
EnsemblENSG00000189403ENSMUSG00000066551
UniProtP09429P63158
RefSeq (mRNA)NM_002128NM_010439
RefSeq (protein)NP_002119NP_034569
Location (UCSC)Chr 13:
31.03 – 31.19 Mb		Chr 5:
149.05 – 149.05 Mb
PubMed search
This box:

High-mobility group protein B1, also known as high-mobility group protein 1 (HMG-1) and amphoterin, is a protein that in humans is encoded by the HMGB1 gene.[1][2]

HMG-1 belongs to high mobility group.

Function

Like the histones, HMGB1 is among the most important chromatin proteins. In the nucleus HMGB1 interacts with nucleosomes, transcription factors, and histones.[3] This nuclear protein organizes the DNA and regulates transcription.[4] After binding, HMGB1 bends DNA, which facilitates the binding of other proteins. HMGB1 supports transcription of many genes in interactions with many transcription factors. It also interacts with nucleosomes to loose packed DNA and remodel the chromatin. Contact with core histones changes the structure of nucleosomes.

The presence of HMGB1 in the nucleus depends on posttranslational modifications. When the protein is not acetylated, it stays in the nucleus, but hyperacetylation on lysine residues causes it to translocate into the cytosol.[4]

Role in inflammation

HMGB1 is secreted by immune cells (like macrophages, monocytes and dendritic cells) through leaderless secretory pathway.[4] Activated macrophages and monocytes secrete HMGB1 as a cytokine mediator of Inflammation.[5] Antibodies that neutralize HMGB1 confer protection against damage and tissue injury during arthritis, colitis, ischemia, sepsis, endotoxemia, and systemic lupus erythematosus.[citation needed] The mechanism of inflammation and damage is binding to TLR4, which mediates HMGB1-dependent activation of macrophage cytokine release. This positions HMGB1 at the intersection of sterile and infectious inflammatory responses.[6][7]

HMGB1 has been proposed as a DNA vaccine adjuvant.[8]

Interactions

HMGB1 has to interact with P53.[9][10]

HMGB1 is an intracellular protein that can translocate to the nucleus where it binds DNA and regulates gene expression. It can also be released from cells, in which extracellular form it can bind the inflammatory receptor RAGE (Receptor for Advanced Glycan Endproducts]. Release from cells seems to involve two distinct processes: necrosis, in which case cell membranes are permeabilized and intracellular constituents may diffuse out of the cell; and some form of active or facilitated secretion induced by signaling through the NFkappaB.

HMGB1 can interact with TLR ligands and cytokines, and activates cells through the multiple surface receptors including TLR2, TLR4, and RAGE.[11]

Interaction via TLR4

Among the receptors of amphoterin includes toll-like receptors. Interaction of HMGB1 and TLR4 results in upregulation of NF-kappa B , which leads to increased production and an release of cytokines in macrophages and in neutrophils for example stimulates release ROS via TLR-dependent activation of NADPH oxidase.[4][12] HMGB1-LPS complex activates TLR4, and leads to binding adapter proteins (MyD88 and others), which leads to signal transduction and activate signaling cascades. In the last line leads to activation of MAPK cascades and NF-kapa B and thus to the production of cytokines and other inflammatory molecules.[13][14]

Clinical significance

HMGB1 has been proposed as a target for cancer therapy.[15]

References

  1. ↑ Ferrari S, Finelli P, Rocchi M, Bianchi ME (July 1996). "The active gene that encodes human high mobility group 1 protein (HMG1) contains introns and maps to chromosome 13". Genomics 35 (2): 367–71. doi:10.1006/geno.1996.0369. PMID 8661151. 
  2. ↑ Chou DK, Evans JE, Jungalwala FB (April 2001). "Identity of nuclear high-mobility-group protein, HMG-1, and sulfoglucuronyl carbohydrate-binding protein, SBP-1, in brain". J. Neurochem. 77 (1): 120–31. doi:10.1046/j.1471-4159.2001.t01-1-00209.x. PMID 11279268. 
  3. ↑ Bianchi ME, Agresti A (October 2005). "HMG proteins: dynamic players in gene regulation and differentiation". Curr. Opin. Genet. Dev. 15 (5): 496–506. doi:10.1016/j.gde.2005.08.007. PMID 16102963. 
  4. ↑ 4.0 4.1 4.2 4.3 Klune JR, Dhupar R, Cardinal J, Billiar TR, Tsung A (2008). "HMGB1: endogenous danger signaling". Mol. Med. 14 (7-8): 476–84. doi:10.2119/2008-00034.Klune. PMC 2323334. PMID 18431461. 
  5. ↑ Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E, Abraham E, Andersson J, Andersson U, Molina PE, Abumrad NN, Sama A, Tracey KJ (July 1999). "HMG-1 as a late mediator of endotoxin lethality in mice". Science 285 (5425): 248–51. doi:10.1126/science.285.5425.248. PMID 10398600. 
  6. ↑ Yang H, Hreggvidsdottir HS, Palmblad K, Wang H, Ochani M, Li J, Lu B, Chavan S, Rosas-Ballina M, Al-Abed Y, Akira S, Bierhaus A, Erlandsson-Harris H, Andersson U, Tracey KJ (June 2010). "A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release". Proc. Natl. Acad. Sci. U.S.A. 107 (26): 11942–7. doi:10.1073/pnas.1003893107. PMC 2900689. PMID 20547845. 
  7. ↑ Yang H, Tracey KJ (2010). "Targeting HMGB1 in inflammation". Biochim. Biophys. Acta 1799 (1-2): 149–56. doi:10.1016/j.bbagrm.2009.11.019. PMID 19948257. 
  8. ↑ Fagone P, Shedlock DJ, Bao H, Kawalekar OU, Yan J, Gupta D, Morrow MP, Patel A, Kobinger GP, Muthumani K, Weiner DB (November 2011). "Molecular adjuvant HMGB1 enhances anti-influenza immunity during DNA vaccination". Gene Ther. 18 (11): 1070–7. doi:10.1038/gt.2011.59. PMID 21544096. 
  9. ↑ Imamura T, Izumi H, Nagatani G, Ise T, Nomoto M, Iwamoto Y, Kohno K (March 2001). "Interaction with p53 enhances binding of cisplatin-modified DNA by high mobility group 1 protein". J. Biol. Chem. 276 (10): 7534–40. doi:10.1074/jbc.M008143200. PMID 11106654. 
  10. ↑ Dintilhac A, Bernués J (March 2002). "HMGB1 interacts with many apparently unrelated proteins by recognizing short amino acid sequences". J. Biol. Chem. 277 (9): 7021–8. doi:10.1074/jbc.M108417200. PMID 11748221. 
  11. ↑ Sims GP, Rowe DC, Rietdijk ST, Herbst R, Coyle AJ (2010). "HMGB1 and RAGE in inflammation and cancer". Annu. Rev. Immunol. 28: 367–88. doi:10.1146/annurev.immunol.021908.132603. PMID 20192808. 
  12. ↑ Park JS, Gamboni-Robertson F, He Q, Svetkauskaite D, Kim JY, Strassheim D et al. (2006). "High mobility group box 1 protein interacts with multiple Toll-like receptors.". Am J Physiol Cell Physiol 290 (3): C917–24. doi:10.1152/ajpcell.00401.2005. PMID 16267105. 
  13. ↑ Bianchi ME (2009). "HMGB1 loves company.". J Leukoc Biol 86 (3): 573–6. doi:10.1189/jlb.1008585. PMID 19414536. 
  14. ↑ Hreggvidsdóttir HS, Lundberg AM, Aveberger AC, Klevenvall L, Andersson U, Harris HE (2012). "High mobility group box protein 1 (HMGB1)-partner molecule complexes enhance cytokine production by signaling through the partner molecule receptor". Mol. Med. 18: 224–30. doi:10.2119/molmed.2011.00327. PMC 3320135. PMID 22076468. 
  15. ↑ Lotze MT, DeMarco RA (December 2003). "Dealing with death: HMGB1 as a novel target for cancer therapy". Curr Opin Investig Drugs 4 (12): 1405–9. PMID 14763124. 

Further reading

External links

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