High Mobility Group Box 1: Biological Functions and Relevance in Oxidative Stress Related Chronic Diseases

Abstract

In the early 1970s, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and named high-mobility group (HMG) proteins. High-mobility group box 1 (HMGB1) is the most studied HMG protein that detects and coordinates cellular stress response. The biological function of HMGB1 depends on its subcellular localization and expression. It plays a critical role in the nucleus and cytoplasm as DNA chaperone, chromosome gatekeeper, autophagy maintainer, and protector from apoptotic cell death. HMGB1 also functions as an extracellular alarmin acting as a damage-associated molecular pattern molecule (DAMP). Recent findings describe HMGB1 as a sophisticated signal of danger, with a pleiotropic function, which is useful as a clinical biomarker for several disorders. HMGB1 has emerged as a mediator in acute and chronic inflammation. Furthermore, HMGB1 targeting can induce beneficial effects on oxidative stress related diseases. This review focus on HMGB1 redox status, localization, mechanisms of release, binding with receptors, and its activities in different oxidative stress-related chronic diseases. Since a growing number of reports show the key role of HMGB1 in socially relevant pathological conditions, to our knowledge, for the first time, here we analyze the scientific literature, evaluating the number of publications focusing on HMGB1 in humans and animal models, per year, from 2006 to 2021 and the number of records published, yearly, per disease and category (studies on humans and animal models).

Changing Perspectives from Oxidative Stress to Redox Signaling—Extracellular Redox Control in Translational Medicine

“…HMGB1 oxidation is a regulated process during physiological inflammation and disease. Many different diseases have been linked to the levels of HMGB1 [63,64]. Interestingly, ongoing research ex vivo and in different mouse models links oxidized HMGB1 to angiogenesis in cancer [65], depression due to neuroinflammation [66] and sepsis, by increasing cell metabolism and the release of pro-inflammatory cytokinestwo hallmarks of sepsis.…”

Role of HMGB1 in Cutaneous Melanoma: State of the Art

“…High mobility group box 1 (HMGB1) is a nuclear protein, encoded by a gene on chromosome 13q12, that acts as a non-histone chromatin-binding protein, with 215 amino acids and a molecular weight of 25-kDa. HMGB1 is composed of two proximal homologous DNA binding domains and a C–terminal ending with residues of glutamic and aspartic acid [ 9 ]. HMGB1 is normally localized in the nucleus, but it can move to the cytosol, or it can be released or actively secreted in the extracellular space by injured cells.…”

“…The translocation of HMGB1 from the nucleus to the cytoplasm is driven by the nuclear localization signals (NLS1 and NLS2) and nuclear export signals (NESs). Exogenous stimuli, which cause injury or death, lead to cellular alarm system activation thus releasing alarmins or pathogen-associated molecular patterns (DAMPs) to signal danger-induced cellular stress [ 9 , 10 ].…”

“…HMGB1 can bind to several extracellular receptors, such as the one for advanced glycation end products (RAGE), Toll-like receptor (TLR) 9, TLR4, TLR2, integrins, mucin domain (TIM-3), and C-X-C chemokine receptor type 4 (CXCR4) [ 9 ]. Given the plethora of possible target receptors for HMGB1, each domain can interact with different molecules and, in particular, residues 150–183 bind to RAGE, a major actor in the beginning and maintenance of the inflammatory process.…”

“…HMGB1 plays a central role in autophagy induction, an endogenous survival mechanism against cell stress [ 14 ]. HMGB1 induces autophagy in the nucleus upregulating the expression of heat shock protein (HSP) 27, while in the extracellular space, once released by cancer cells, it binds RAGE inducing in turn autophagocytic activity in nearby cells [ 9 ]. It is demonstrated that cancer can upregulate autophagy, which leads to drug resistance thwarting chemotherapy [ 11 ].…”