Biology:HMGB1

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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]

ADP-ribosylation of HMGB1 by PARP1 inhibits removal of apoptotic cells, thereby sustaining inflammation.[10] TLR4 binding by HMGB1 or LPS (lipopolysaccharide) sustains ADP-ribosylation of HMGB1 by PARP1 thereby serving as an amplification loop for inflammation.[10]

HMGB1 has been proposed as a DNA vaccine adjuvant.[11] 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.[12]

Interactions

HMGB1 has to interact with p53.[13][14]

HMGB1 is a nuclear protein that binds to DNA and acts as an architectural chromatin-binding factor. It can also be released from cells, in which extracellular form it can bind the inflammatory receptor RAGE (Receptor for Advanced Glycation End-products) and Toll-like receptors (TLRs). 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 also translocates to the cytosol under stressful conditions such as increased ROS inside the cells. Under such conditions, HMGB1 promotes cell survival by sustaining autophagy through interactions with beclin-1. It is largely considered as an antiapoptotic protein.

HMGB1 can interact with TLR ligands and cytokines, and activates cells through the multiple surface receptors including TLR2, TLR4, and RAGE.[15]

Interaction via TLR4

Some actions of HMGB1 are mediated through the toll-like receptors (TLRs).[16] 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][17] 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.[18][19]

Clinical significance

HMGB1 has been proposed as a target for cancer therapy,[20] as a vector for reducing inflammation from SARS-CoV-2 infection. [21] and as a biomarker for post-COVID-19 condition.[22]

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.[23] 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.[23] Thus impairment of HMGB1 function appears to have a key role in the pathogenesis of SCA1.

Recently, a study provided evidence of an association between raised levels of HMGB1 and attention to detail and systemizing in unmedicated children with high-functioning Autism spectrum disorder (ASD), suggesting that inflammatory processes mediated by HMGB1 may play a role in the disruption of neurobiological mechanisms regulating cognitive processes in ASD.[24] In this study, HMGB1 serum concentrations in children with ASD were found significantly higher than those of typically developing children. Additionally, HMGB1 serum concentrations were positively correlated with the Autistic quotient (AQ) attention to detail score and the Systemizing Quotient (SQ) total score in the ASD group.[25] However, comprehensive evidence in children is limited, highlighting the need for in-depth research towards understanding possible mechanisms linking HMGB1 with the core features of ASD. Nevertheless, it has been suggested that HMGB1 could be a reliable inflammatory marker, explaining the link between inflammatory processes and several autistic traits, and therefore a possible therapeutic target in this neurodevelopmental disorder.


References

  1. ↑ "The active gene that encodes human high mobility group 1 protein (HMG1) contains introns and maps to chromosome 13". Genomics 35 (2): 367–71. July 1996. doi:10.1006/geno.1996.0369. PMID 8661151. 
  2. ↑ "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. April 2001. doi:10.1046/j.1471-4159.2001.t01-1-00209.x. PMID 11279268. 
  3. ↑ "HMG proteins: dynamic players in gene regulation and differentiation". Current Opinion in Genetics & Development 15 (5): 496–506. October 2005. doi:10.1016/j.gde.2005.08.007. PMID 16102963. 
  4. ↑ 4.0 4.1 4.2 4.3 "HMGB1: endogenous danger signaling". Molecular Medicine 14 (7–8): 476–84. 2008. doi:10.2119/2008-00034.Klune. PMID 18431461. 
  5. ↑ "Single-molecule studies of high-mobility group B architectural DNA bending proteins". Biophysical Reviews 9 (1): 17–40. February 2017. doi:10.1007/s12551-016-0236-4. PMID 28303166. 
  6. ↑ "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. February 2013. doi:10.1093/nar/gks1294. PMID 23293004. 
  7. ↑ "HMG-1 as a late mediator of endotoxin lethality in mice". Science 285 (5425): 248–51. July 1999. doi:10.1126/science.285.5425.248. PMID 10398600. 
  8. ↑ "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. June 2010. doi:10.1073/pnas.1003893107. PMID 20547845. Bibcode: 2010PNAS..10711942Y. 
  9. ↑ "Targeting HMGB1 in inflammation". Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 1799 (1–2): 149–56. 2010. doi:10.1016/j.bbagrm.2009.11.019. PMID 19948257. 
  10. ↑ 10.0 10.1 "Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases". Cells 9 (1): 41. 2019. doi:10.3390/cells9010041. PMID 31877876. 
  11. ↑ "Molecular adjuvant HMGB1 enhances anti-influenza immunity during DNA vaccination". Gene Therapy 18 (11): 1070–7. November 2011. doi:10.1038/gt.2011.59. PMID 21544096. 
  12. ↑ "HMGB1 mediates endogenous TLR2 activation and brain tumor regression". PLOS Medicine 6 (1): e10. January 2009. doi:10.1371/journal.pmed.1000010. PMID 19143470. 
  13. ↑ "Interaction with p53 enhances binding of cisplatin-modified DNA by high mobility group 1 protein". The Journal of Biological Chemistry 276 (10): 7534–40. March 2001. doi:10.1074/jbc.M008143200. PMID 11106654. 
  14. ↑ "HMGB1 interacts with many apparently unrelated proteins by recognizing short amino acid sequences". The Journal of Biological Chemistry 277 (9): 7021–8. March 2002. doi:10.1074/jbc.M108417200. PMID 11748221. 
  15. ↑ "HMGB1 and RAGE in inflammation and cancer". Annual Review of Immunology 28: 367–88. 2010. doi:10.1146/annurev.immunol.021908.132603. PMID 20192808. 
  16. ↑ "RAGE and TLRs: relatives, friends or neighbours?". Molecular Immunology 56 (4): 739–44. December 2013. doi:10.1016/j.molimm.2013.07.008. PMID 23954397. 
  17. ↑ "High mobility group box 1 protein interacts with multiple Toll-like receptors". American Journal of Physiology. Cell Physiology 290 (3): C917-24. March 2006. doi:10.1152/ajpcell.00401.2005. PMID 16267105. 
  18. ↑ "HMGB1 loves company". Journal of Leukocyte Biology 86 (3): 573–6. September 2009. doi:10.1189/jlb.1008585. PMID 19414536. 
  19. ↑ "High mobility group box protein 1 (HMGB1)-partner molecule complexes enhance cytokine production by signaling through the partner molecule receptor". Molecular Medicine 18 (2): 224–30. March 2012. doi:10.2119/molmed.2011.00327. PMID 22076468. 
  20. ↑ "Dealing with death: HMGB1 as a novel target for cancer therapy". Current Opinion in Investigational Drugs 4 (12): 1405–1409. December 2003. PMID 14763124. 
  21. ↑ "Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19?". Molecular Medicine 26 (1): 42. May 2020. doi:10.1186/s10020-020-00172-4. PMID 32380958. 
  22. ↑ "Long-term perturbation of the peripheral immune system months after SARS-CoV-2 infection". BMC Medicine 20 (1): 26. January 2022. doi:10.1186/s12916-021-02228-6. PMID 35027067. 
  23. ↑ 23.0 23.1 "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. January 2015. doi:10.15252/emmm.201404392. PMID 25510912. 
  24. ↑ "Increased serum concentrations of high mobility group box 1 (HMGB1) protein in children with Autism Spectrum Disorder". Children 8 (6): 478. 2021. doi:10.3390/children8060478. PMID 34198762. 
  25. ↑ "Increased serum concentrations of high mobility group box 1 (HMGB1) protein in children with Autism Spectrum Disorder". Children 8 (6): 478. 2021. doi:10.3390/children8060478. PMID 34198762. 

Further reading

External links



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