The mechanism of HMGB1 secretion and release

Abstract

High mobility group box 1 (HMGB1) is a nonhistone nuclear protein that has multiple functions according to its subcellular location. In the nucleus, HMGB1 is a DNA chaperone that maintains the structure and function of chromosomes. In the cytoplasm, HMGB1 can promote autophagy by binding to BECN1 protein. After its active secretion or passive release, extracellular HMGB1 usually acts as a damage-associated molecular pattern (DAMP) molecule, regulating inflammation and immune responses through different receptors or direct uptake. The secretion and release of HMGB1 is fine-tuned by a variety of factors, including its posttranslational modification (e.g., acetylation, ADP-ribosylation, phosphorylation, and methylation) and the molecular machinery of cell death (e.g., apoptosis, pyroptosis, necroptosis, alkaliptosis, and ferroptosis). In this minireview, we introduce the basic structure and function of HMGB1 and focus on the regulatory mechanism of HMGB1 secretion and release. Understanding these topics may help us develop new HMGB1-targeted drugs for various conditions, especially inflammatory diseases and tissue damage.

Fig. 1. The structure and modification of HMGB1.

HMGB1 consists of three domains: two DNA binding domains (Box A and Box B), a C-terminus and an N-terminus. HMGB1 undergoes various posttranslational modifications after cell activation induced by external stimuli, resulting in its translocation from the nucleus to the cytoplasm and finally its release. Ac, acetylation; Ar, ADP-ribosylation; Cys, cysteine; Gly, N-glycosylation; Me, methylation; NLS1/2, nuclear localization signal 1/2; Ox, oxidation; P, phosphorylation.

Fig. 2. Active secretion of HMGB1 during stress.

HMGB1 secretion is mediated by secretory lysosomes, which can be triggered by a variety of cytokines, signaling pathways, and cell–cell interactions.

Fig. 3. Passive release of HMGB1 during cell death.

HMGB1 is a typical damage-associated molecular pattern (DAMP) that can be passively released during various types of cell death, such as pyroptosis, necrosis, apoptosis, necroptosis, ferroptosis, NETosis, and lysosome-mediated and autophagy-dependent cell death.