Immunological Significance of HMGB1 Post-Translational Modification and Redox Biology

Abstract

Most extracellular proteins are secreted via the classical endoplasmic reticulum (ER)/Golgi-dependent secretion pathway; however, some proteins, including a few danger-associated molecular patterns (DAMPs), are secreted via non-classical ER/Golgi-independent secretion pathways. The evolutionarily conserved high mobility group box1 (HMGB1) is a ubiquitous nuclear protein that can be released by almost all cell types. HMGB1 lacks signal peptide and utilizes diverse non-canonical secretion mechanisms for its extracellular export. Although the post-translational modifications of HMGB1 were demonstrated, the oxidation of HMGB1 and secretion mechanisms are not highlighted yet. We currently investigated that peroxiredoxins I and II (PrxI/II) induce the intramolecular disulfide bond formation of HMGB1 in the nucleus. Disulfide HMGB1 is preferentially transported out of the nucleus by binding to the nuclear exportin chromosome-region maintenance 1 (CRM1). We determined the kinetics of HMGB1 oxidation in bone marrow-derived macrophage as early as a few minutes after lipopolysaccharide treatment, peaking at 4 h while disulfide HMGB1 accumulation was observed within the cells, starting to secrete in the late time point. We have shown that HMGB1 oxidation status, which is known to determine the biological activity in extracellular HMGB1, is crucial for the secretion of HMGB1 from the nucleus. This review summarizes selected aspects of HMGB1 redox biology relevant to the induction and propagation of inflammatory diseases. We implicate the immunological significance and the need for novel HMGB1 inhibitors through mechanism-based studies.

The Immune Tolerance Role of the HMGB1-RAGE Axis

“…Active secretion of HMGB1 occurs through the extensive post-translational modifications (PTM) such as acetylation, phosphorylation, methylation and oxidation that determine the localization of HMGB1. PTM-mediated active secretion of HMGB1 is mediated through secretory lysosomes [ 28 ]. The oxidation status of HMGB1 and HMGB1 secretion kinetics also influences its immune function [ 28 ].…”

“…PTM-mediated active secretion of HMGB1 is mediated through secretory lysosomes [ 28 ]. The oxidation status of HMGB1 and HMGB1 secretion kinetics also influences its immune function [ 28 ]. Although the exact active secretion mechanism of HMGB1 remains elusive, a recent study has revealed that C5a engagement with its receptor C5aR2 in macrophages upon infection induces upregulation of HMGB1 expression and release through intracellular signaling [ 29 ] ( Figure 1 ).…”

Role of HMGB1 in Chemotherapy-Induced Peripheral Neuropathy

“…The active secretion of HMGB1 is triggered by microbial pathogens such as lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid (poly(I:C)) [ 44 , 52 , 54 ], or endogenous substances, such as ROS [ 55 ], reactive nitrogen species (RNS) [ 56 ], hyperglycemia [ 53 ], inflammatory cytokines (e.g., TNF-α [ 49 ], interferon (IFN)-α [ 54 ], INF-γ [ 57 ], ATP [ 19 , 58 ], nitric oxide [ 54 ], calcium phosphate-based mineralo-organic particles [ 46 ], and also by cell-to-cell interaction [ 47 ]. Cytoplasmic translocation of nuclear HMGB1 is triggered and/or modulated by post-translational molecular modifications of HMGB1, such as acetylation [ 39 , 59 ], phosphorylation [ 60 ], ADP-ribosylation [ 61 ], methylation [ 62 ], glycosylation [ 63 ], and ROS-induced oxidation [ 64 ] ( Figure 1 C). The interaction between HMGB1 and chromosome-region maintenance 1 (CRM1), also known as exportin-1, plays a key role in the cytoplasmic translocation of nuclear HMGB1.…”

“…The interaction between HMGB1 and chromosome-region maintenance 1 (CRM1), also known as exportin-1, plays a key role in the cytoplasmic translocation of nuclear HMGB1. The cytoplasmic HMGB1 is packaged in secretory lysosomes and then released to the extracellular space ( Figure 1 C), while the classical endoplasmic reticulum-Golgi secretory pathway is not involved in the HMGB1 secretion [ 64 , 65 ].…”

Dendrimers as Modulators of Brain Cells

“…HMGB1 acts as an alarmin both extra- and intra-cellularly [ 39 , 40 , 41 , 42 ]. Compartmentalization determines HMGB1 function, which is tightly regulated by its molecular binding partners and redox state [ 43 , 44 , 45 ]. Dendritic polyglycerol sulfates (dPGS) have considerable structural similarities with anticoagulant heparin (sulfated form), which can interact with HMGB1.…”