HMGB1

High-mobility group protein B1, also known as high-mobility group protein 1 (HMG-1), is a is_associated_with::protein that in humans is encoded by the HMGB1 is_associated_with::gene.

HMG-1 belongs to is_associated_with::high mobility group.

Function
Like the is_associated_with::histones, HMGB1 is among the most important chromatin proteins. In the nucleus HMGB1 interacts with is_associated_with::nucleosomes, transcription factors, and is_associated_with::histones. This nuclear protein organizes the DNA and regulates transcription. After binding, HMGB1 bends is_associated_with::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.

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

HMGB1 has been proposed as a is_associated_with::DNA vaccine is_associated_with::adjuvant.

Interactions
HMGB1 has to interact with is_associated_with::P53.

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 is_associated_with::NFkappaB.

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

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

Clinical significance
HMGB1 has been proposed as a target for cancer therapy.