Like the histones, HMGB1 is among the most important chromatin proteins. In the nucleus HMGB1 interacts with nucleosomes, transcription factors, and histones. This nuclear protein organizes the DNA and regulates transcription. 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 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. HMGB1 has been shown to play an important role in helping the RAG endonuclease form a paired complex during VJ recombination.
HMGB1 has to interact with P53. 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 and Toll-like receptors. 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.
Interaction via TLR4
Some actions of HMGB1 are mediated through the toll-like receptors. 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. HMGB1-LPS complex activates TLR4, and causes the binding of adapter proteins, 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.
Clinical significance
HMGB1 has been proposed as a target for cancer therapy, and as a vector for reducing inflammation from SARS-CoV-2 infection. The neurodegenerative diseasespinocerebellar ataxia type 1 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. 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. Thus impairment of HMGB1 function appears to have a key role in the pathogenesis of SCA1.
