The redox-sensitive protein HMGB1: intracellular and extracellular roles

HMGB1 is a non-histone nuclear protein that is primarily located in the nucleus. It can be translocated to the cytoplasm and secreted into the extracellular space upon stimulation. In the nucleus, HMGB1 functions as a DNA chaperone; in the cytoplasm, it participates in autophagy and mitochondrial homeostasis; and in the extracellular environment, it acts as a damage-associated molecular pattern. HMGB1 consists of three cysteine residues (C²³, C⁴⁵ and C¹⁰⁶) and is a redox-sensitive protein that exists in distinct redox isoforms: reduced (Re-HMGB1), disulfide (Ds-HMGB1), oxidized (Ox-HMGB1) and dimerized (Di-HMGB1). The localization-specific functions of HMGB1 are regulated by its redox state, which is involved in preventing DNA damage, inflammation, cell death and survival, and various inflammatory disorders. This Review describes the oxidation mechanisms of HMGB1 and summarizes its functional roles in the nucleus, cytoplasm and extracellular space depending on its redox status. We further describe the oxidation states of HMGB1 released during different forms of cell death, the distinct redox isoform of HMGB1 and its possible association with various diseases. This Review provides insights into therapeutic strategies targeting redox-sensitive damage-associated molecular patterns in inflammatory and autoimmune pathologies.