High mobility group box 1 protein, also known ashigh-mobility group protein 1 (HMG-1) andamphoterin, is aprotein that in humans is encoded by theHMGB1gene.[3][4]
Like thehistones, HMGB1 is among the most important chromatin proteins. In thenucleus HMGB1 interacts withnucleosomes, transcription factors, andhistones.[5] This nuclear protein organizes the DNA and regulates transcription.[6] After binding, HMGB1 bends[7]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.[6]
ADP-ribosylation of HMGB1 byPARP1 inhibits removal ofapoptotic cells, thereby sustaining inflammation.[12] TLR4 binding by HMGB1 orlipopolysaccharide (LPS) sustains ADP-ribosylation of HMGB1 by PARP1 thereby serving as an amplification loop for inflammation.[12]
HMGB1 has been proposed as aDNA vaccineadjuvant.[13] 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.[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, an extracellular form in which it may bind to toll-like receptors (TLRs) or an inflammatory receptor called the receptor for advanced glycation end-productsRAGE. 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 theNF-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 includingTLR2,TLR4, and RAGE.[17]
Some actions of HMGB1 are mediated through thetoll-like receptors (TLRs).[18] Interaction between HMGB1 and TLR4 results in upregulation ofNF-κB, which leads to increased production and release ofcytokines. HMGB1 is also able to interact with TLR4 onneutrophils to stimulate the production ofreactive oxygen species by NADPH oxidase.[6][19] HMGB1-LPS complex activates TLR4, and causes the binding of adapter proteins (MyD88 and others), leading tosignal transduction and the activation of various signaling cascades. The downstream effect of this signaling is to activateMAPK and NF-κB, and thus cause the production of inflammatory molecules such as cytokines.[20][21]
HMGB1 has been proposed as a target for cancer therapy,[22] as well as a vector for reducing inflammation fromSARS-CoV-2 infection.[23] It also serves as a biomarker forpost-COVID-19 condition.[24]
Theneurodegenerative diseasespinocerebellar ataxia type 1 (SCA1) is caused bymutation in theataxin 1 gene. In a mouse model of SCA1, mutant ataxin 1 protein mediated the reduction or inhibition of HMGB1 in themitochondria ofneurons.[25] HMGB1 regulatesDNA architectural changes essential for repair ofDNA 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 theneuropathology and the motor defects of the SCA1 mice, and also extended their lifespan.[25] 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.[26] 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.[27] 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.
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^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.PMID8661151.
^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 (inactive 13 November 2025).PMID11279268.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^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.PMID16102963.
^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.PMID10398600.
^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.PMID23954397.
^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.PMID16267105.S2CID21350171.
^Lotze MT, DeMarco RA (December 2003). "Dealing with death: HMGB1 as a novel target for cancer therapy".Current Opinion in Investigational Drugs.4 (12):1405–1409.PMID14763124.
Thomas JO, Travers AA (March 2001). "HMG1 and 2, and related 'architectural' DNA-binding proteins".Trends in Biochemical Sciences.26 (3):167–74.doi:10.1016/S0968-0004(01)01801-1.PMID11246022.
Andersson U, Erlandsson-Harris H, Yang H, Tracey KJ (December 2002). "HMGB1 as a DNA-binding cytokine".Journal of Leukocyte Biology.72 (6):1084–91.doi:10.1189/jlb.72.6.1084.PMID12488489.S2CID11409274.
Erlandsson Harris H, Andersson U (June 2004). "Mini-review: The nuclear protein HMGB1 as a proinflammatory mediator".European Journal of Immunology.34 (6):1503–12.doi:10.1002/eji.200424916.PMID15162419.S2CID11470463.
Jiang W, Pisetsky DS (January 2007). "Mechanisms of Disease: the role of high-mobility group protein 1 in the pathogenesis of inflammatory arthritis".Nature Clinical Practice. Rheumatology.3 (1):52–8.doi:10.1038/ncprheum0379.PMID17203009.S2CID428632.
Ellerman JE, Brown CK, de Vera M, Zeh HJ, Billiar T, Rubartelli A, Lotze MT (May 2007). "Masquerader: high mobility group box-1 and cancer".Clinical Cancer Research.13 (10):2836–48.doi:10.1158/1078-0432.CCR-06-1953.PMID17504981.S2CID32922516.
Bernués J, Espel E, Querol E (May 1986). "Identification of the core-histone-binding domains of HMG1 and HMG2".Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression.866 (4):242–51.doi:10.1016/0167-4781(86)90049-7.PMID3697355.
Rasmussen RK, Ji H, Eddes JS, Moritz RL, Reid GE, Simpson RJ, Dorow DS (1997). "Two-dimensional electrophoretic analysis of human breast carcinoma proteins: mapping of proteins that bind to the SH3 domain of mixed lineage kinase MLK2".Electrophoresis.18 (3–4):588–98.doi:10.1002/elps.1150180342.PMID9150946.S2CID37336552.
Nagaki S, Yamamoto M, Yumoto Y, Shirakawa H, Yoshida M, Teraoka H (May 1998). "Non-histone chromosomal proteins HMG1 and 2 enhance ligation reaction of DNA double-strand breaks".Biochemical and Biophysical Research Communications.246 (1):137–41.Bibcode:1998BBRC..246..137N.doi:10.1006/bbrc.1998.8589.PMID9600082.
Claudio JO, Liew CC, Dempsey AA, Cukerman E, Stewart AK, Na E, Atkins HL, Iscove NN, Hawley RG (May 1998). "Identification of sequence-tagged transcripts differentially expressed within the human hematopoietic hierarchy".Genomics.50 (1):44–52.doi:10.1006/geno.1998.5308.PMID9628821.
