# The redox-sensitive protein HMGB1: intracellular and extracellular roles

## TL;DR

This review explains how the protein HMGB1, which exists in different oxidation forms, plays various roles in the cell and contributes to inflammation and disease.

## Contribution

The paper provides a comprehensive overview of HMGB1's redox-dependent functions and their implications in inflammation and disease.

## Key findings

- HMGB1 exists in multiple redox forms (Re, Ds, Ox, Di) with distinct functional roles.
- Ds-HMGB1 is associated with chronic inflammation and diseases like sepsis and cancer.
- Re-HMGB1 aids in tissue repair, while Di-HMGB1 enhances immune activity.

## Abstract

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.

This Review explores the role of HMGB1, a protein involved in immune responses and inflammation. HMGB1 can exist in different forms depending on its oxidation state, which affects its function. The study addresses how these forms influence inflammation and disease. Researchers found that HMGB1 can act as a danger signal (damage-associated molecular pattern) when released from cells, triggering immune responses. They outline HMGB1’s behavior under different conditions, focusing on its redox states. These states include reduced (Re-HMGB1), disulfide (Ds-HMGB1) and oxidized (Ox-HMGB1) forms, each playing distinct roles in inflammation and cell death. Ds-HMGB1 is linked to chronic inflammation and diseases such as sepsis and cancer. By contrast, Re-HMGB1 helps with tissue repair. In addition, a dimerized form (Di-HMGB1) was recently identified, showing enhanced immune-boosting activity. Understanding these roles could lead to new treatments for inflammatory diseases.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.