HMGB1

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High mobility group box 1 protein, 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 the high mobility group and contains a HMG-box domain.

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[5] 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 loosen 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]

HMGB1 has been shown to play an important role in helping the RAG endonuclease form a paired complex during V(D)J recombination.[6]

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.[7] 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 consists of binding to TLR2 and TLR4, which mediates HMGB1-dependent activation of macrophage cytokine release. This positions HMGB1 at the intersection of sterile and infectious inflammatory responses.[8][9]

HMGB1 has been proposed as a DNA vaccine adjuvant.[10] HMGB1 released from tumour cells was demonstrated to mediate anti-tumour immune responses by activating Toll-like receptor 2 (TLR2) signaling on bone marrow-derived GBM-infiltrating DCs.[11]

Interactions

HMGB1 has to interact with P53.[12][13]

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 Glycation End-products). 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 NF-κB.

HMGB1 can interact with TLR ligands and cytokines, and activates cells through the multiple surface receptors including TLR2, TLR4, and RAGE.[14]

Interaction via TLR4

Some actions of HMGB1 are mediated through the toll-like receptors (TLRs).[15] Interaction between HMGB1 and TLR4 results in upregulation of NF-κB, which leads to increased production and release of cytokines. HMGB1 is also able to interact with TLR4 on neutrophils to stimulate the production of reactive oxygen species by NADPH oxidase.[4][16] HMGB1-LPS complex activates TLR4, and causes the binding of adapter proteins (MyD88 and others), leading to signal transduction and the activation of various signaling cascades. The downstream effect of this signaling is to activate MAPK and NF-κB, and thus cause the production of inflammatory molecules such as cytokines.[17][18]

Clinical significance

HMGB1 has been proposed as a target for cancer therapy.[19]

The neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) is caused by mutation in the ataxin 1 gene. In a mouse model of SCA1, mutant ataxin 1 protein mediated the reduction or inhibition of HMGB1 in the mitochondria of neurons.[20] HMGB1 regulates DNA architectural changes essential for repair of DNA damage. In the SCA1 mouse model, over-expression of the HMGB1 protein by means of an introduced virus vector bearing the HMGB1 gene facilitated repair of the mitochondrial DNA damage, ameliorated the neuropathology and the motor defects of the SCA1 mice, and also extended their lifespan.[20] Thus impairment of HMGB1 function appears to have a key role in the pathogenesis of SCA1.

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". Journal of Neurochemistry. 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". Current Opinion in Genetics & Development. 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". Molecular Medicine. 14 (7–8): 476–84. doi:10.2119/2008-00034.Klune. PMC 2323334. PMID 18431461.
  5. ↑ Murugesapillai D, McCauley MJ, Maher LJ, Williams MC (February 2017). "Single-molecule studies of high-mobility group B architectural DNA bending proteins". Biophysical Reviews. 9 (1): 17–40. doi:10.1007/s12551-016-0236-4. PMID 28303166.
  6. ↑ Ciubotaru M, Trexler AJ, Spiridon LN, Surleac MD, Rhoades E, Petrescu AJ, Schatz DG (February 2013). "RAG and HMGB1 create a large bend in the 23RSS in the V(D)J recombination synaptic complexes". Nucleic Acids Research. 41 (4): 2437–54. doi:10.1093/nar/gks1294. PMC 3575807. PMID 23293004.
  7. ↑ 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.
  8. ↑ 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". Proceedings of the National Academy of Sciences of the United States of America. 107 (26): 11942–7. doi:10.1073/pnas.1003893107. PMC 2900689. PMID 20547845.
  9. ↑ Yang H, Tracey KJ (2010). "Targeting HMGB1 in inflammation". Biochimica et Biophysica Acta. 1799 (1–2): 149–56. doi:10.1016/j.bbagrm.2009.11.019. PMC 4533842. PMID 19948257.
  10. ↑ 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 Therapy. 18 (11): 1070–7. doi:10.1038/gt.2011.59. PMC 4141626. PMID 21544096.
  11. ↑ Curtin JF, Liu N, Candolfi M, Xiong W, Assi H, Yagiz K, Edwards MR, Michelsen KS, Kroeger KM, Liu C, Muhammad AK, Clark MC, Arditi M, Comin-Anduix B, Ribas A, Lowenstein PR, Castro MG (January 2009). "HMGB1 mediates endogenous TLR2 activation and brain tumor regression". PLoS Medicine. 6 (1): e10. doi:10.1371/journal.pmed.1000010. PMC 2621261. PMID 19143470.
  12. ↑ 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". The Journal of Biological Chemistry. 276 (10): 7534–40. doi:10.1074/jbc.M008143200. PMID 11106654.
  13. ↑ Dintilhac A, Bernués J (March 2002). "HMGB1 interacts with many apparently unrelated proteins by recognizing short amino acid sequences". The Journal of Biological Chemistry. 277 (9): 7021–8. doi:10.1074/jbc.M108417200. PMID 11748221.
  14. ↑ Sims GP, Rowe DC, Rietdijk ST, Herbst R, Coyle AJ (2010). "HMGB1 and RAGE in inflammation and cancer". Annual Review of Immunology. 28: 367–88. doi:10.1146/annurev.immunol.021908.132603. PMID 20192808.
  15. ↑ Ibrahim ZA, Armour CL, Phipps S, Sukkar MB (December 2013). "RAGE and TLRs: relatives, friends or neighbours?". Molecular Immunology. 56 (4): 739–44. doi:10.1016/j.molimm.2013.07.008. PMID 23954397.
  16. ↑ Park JS, Gamboni-Robertson F, He Q, Svetkauskaite D, Kim JY, Strassheim D, Sohn JW, Yamada S, Maruyama I, Banerjee A, Ishizaka A, Abraham E (March 2006). "High mobility group box 1 protein interacts with multiple Toll-like receptors". American Journal of Physiology. Cell Physiology. 290 (3): C917–24. doi:10.1152/ajpcell.00401.2005. PMID 16267105.
  17. ↑ Bianchi ME (September 2009). "HMGB1 loves company". Journal of Leukocyte Biology. 86 (3): 573–6. doi:10.1189/jlb.1008585. PMID 19414536.
  18. ↑ Hreggvidsdóttir HS, Lundberg AM, Aveberger AC, Klevenvall L, Andersson U, Harris HE (March 2012). "High mobility group box protein 1 (HMGB1)-partner molecule complexes enhance cytokine production by signaling through the partner molecule receptor". Molecular Medicine. 18: 224–30. doi:10.2119/molmed.2011.00327. PMC 3320135. PMID 22076468.
  19. ↑ Lotze MT, DeMarco RA (December 2003). "Dealing with death: HMGB1 as a novel target for cancer therapy". Current Opinion in Investigational Drugs. 4 (12): 1405–9. PMID 14763124.
  20. ↑ 20.0 20.1 Ito H, Fujita K, Tagawa K, Chen X, Homma H, Sasabe T, Shimizu J, Shimizu S, Tamura T, Muramatsu S, Okazawa H (January 2015). "HMGB1 facilitates repair of mitochondrial DNA damage and extends the lifespan of mutant ataxin-1 knock-in mice". EMBO Molecular Medicine. 7 (1): 78–101. doi:10.15252/emmm.201404392. PMC 4309669. PMID 25510912.

Further reading

External links

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