The mechanism of HMGB1 secretion and release

Ruochan Chen,Daolin Tang,Rui Kang

doi:10.1038/s12276-022-00736-w

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.

Highlights

In 1973, Ernest Johns, Graham Goodwin and colleagues extracted a set of nonhistone proteins from calf thymus chromatin[1,2]
High mobility group box 1 (HMGB1) is mainly located in the nucleus and binds to chromatin, but it can shuttle from the nucleus to the cytoplasm under various stress conditions and into the extracellular space, for example, when induced by elevated reactive oxygen species (ROS) production during porcine circovirus type 2 infection[8,9]
The interaction between infiltrating uveitogenic T cells and retinal cells can induce rapid release of HMGB1 through the Fas cell surface death receptor (Fas)/Fas ligand inflammatory signaling pathway[179]. These findings further indicate that HMGB1 is a signaling mediator that coordinates the communication between different cells during an immune response

Summary

Introduction

In 1973, Ernest Johns, Graham Goodwin and colleagues extracted a set of nonhistone proteins from calf thymus chromatin[1,2]. In response to infection and tissue damage, HMGB1 can be actively secreted and passively released outside cells, where they function as damage-associated molecular pattern molecules (DAMPs) to mediate inflammation and immune responses[15,16]. In addition to acetylation[33], other modifications, such as methylation, N-glycosylation, phosphorylation, and oxidation, can regulate the translocation and release of HMGB1 to the extracellular space in response to various stresses[20,27,34,35,36,37,38,39,40].

Results

Conclusion