Post-Translational Modification of HMGB1 Disulfide Bonds in Stimulating and Inhibiting Inflammation

Abstract

High mobility group box 1 protein (HMGB1), a highly conserved nuclear DNA-binding protein, is a “damage-associated molecular pattern” molecule (DAMP) implicated in both stimulating and inhibiting innate immunity. As reviewed here, HMGB1 is an oxidation-reduction sensitive DAMP bearing three cysteines, and the post-translational modification of these residues establishes its proinflammatory and anti-inflammatory activities by binding to different extracellular cell surface receptors. The redox-sensitive signaling mechanisms of HMGB1 also occupy an important niche in innate immunity because HMGB1 may carry other DAMPs and pathogen-associated molecular pattern molecules (PAMPs). HMGB1 with DAMP/PAMP cofactors bind to the receptor for advanced glycation end products (RAGE) which internalizes the HMGB1 complexes by endocytosis for incorporation in lysosomal compartments. Intra-lysosomal HMGB1 disrupts lysosomal membranes thereby releasing the HMGB1-transported molecules to stimulate cytosolic sensors that mediate inflammation. This HMGB1-DAMP/PAMP cofactor pathway slowed the development of HMGB1-binding antagonists for diagnostic or therapeutic use. However, recent discoveries that HMGB1 released from neurons mediates inflammation via the TLR4 receptor system, and that cancer cells express fully oxidized HMGB1 as an immunosuppressive mechanism, offer new paths to targeting HMGB1 for inflammation, pain, and cancer.

Paracrine signal emanating from stressed cardiomyocytes aggravates inflammatory microenvironment in diabetic cardiomyopathy

“…With regards to HMGB1 secretion, it occurs via ER-independent secretory pathways and depends on its post-translational modifications such as acetylation and its redox state, specifically disulfide bonds ( Andersson et al., 2021 ; Kwak et al., 2020 ). In immune cells, its cytoplasmic translocation and subsequent release require acetylation in the nuclear localization sequence ( Magna and Pisetsky, 2014 ; Ramadan et al., 2017 ) via Janus kinases/signal transducer and activator of transcription-1 or poly(ADP-ribose) polymerase-1 pathway ( Lu et al., 2014 ; Yang et al., 2014 ).…”

The Role of HMGB1 in Rheumatic Diseases

“…This is consistent with the situation that Cys106 is in the reduced state during necrosis and in the oxidation state during apoptosis. Furthermore, homo-dimerization of HMGB1 at Cys106 has been found in the nucleus and extracellular, but its biological significance remains unclear ( 21 ).…”

“…Activated immune cells [macrophages, dendritic cells (DCs)] and tissue cells (endothelial cells neurons, astrocytes) actively secreted HMGB1 ( 21 ). The release of HMGB1 from the nucleus to the cytoplasm depends on the activation of the Janus kinase (JAK) signal transducer and activator of transcription 1 (STAT1) pathway, or the balance of the histone acetylase (HAT) activity and histone deacetylase (HDAC) activity, or the formation of disulfide HMGB1 via peroxidase I and II ( 14 , 21 ). Then HMGB1 was packaged in vesicles and released extracellular via lysosomal pathway ( 6 ).…”

“…RAGE was the first HMGB1 receptor to be discovered. HMGB1 with other pro-inflammatory partner molecules could interact with RAGE to enter the endosomal and lysosomal system, then HMGB1 disrupted the lysosomal membrane at low pH, and the partner molecules bound to homologous receptors in the cytosol to mediate the synthesis of pro-inflammatory mediators ( 21 ). HMGB1 could also interact with TLRs (TLR2, TLR4) to activate the NF-κB and IRF pathways and then produce cytokines and chemokines for the inflammation and immune response ( 30 ).…”

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

“…In this regard, it has been previously demonstrated that oxidative stress due to cigarette smoke exposure reduces HDAC2, HDAC3, and sirtuin 1 (SIRT1) expression/activity [ 11 , 12 , 13 ]. Agents such as metformin, resveratrol, and curcumin, enhancing SIRT1 deacetylase activity, lead to the decrease of extracellular HMGB1 release and the inhibition of HMGB1-dependent inflammation [ 14 ]. Depending on the nature of cellular insults and cytotypes, the release mechanisms of HMGB1 are controlled at various levels, including activation of transcription factors such as NF-κB and the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing protein three (NLRP3) inflammasome.…”