Post-translational modifications of high mobility group box 1 and cancer

Abstract

Post-translational modifications (PTMs) of High mobility group box 1 (HMGB1) have not been investigated as extensively as those of other HMG proteins but accumulating evidence has shown the remarkable biological significances induced by the post-translational: acetylation, methylation and phosphorylation, oxidation, glycosylation and ADP-ribosylation of the HMGB1 to modulate its interactions with DNA and other proteins. Although HMGB1 is localized in the nucleus in almost all cells at baseline, it can be rapidly mobilized to other sites within the cell, including the cytoplasm and mitochondria, as well as into the extracellular; hence there is an increasing interest by researches into the complex relationship between the PTMs of HMGB1 protein and its diverse biological activities. The PTMs of HMGB1 could also have effects on gene expression following changes in its DNA-binding properties and in extracellular environment displays immunological activity and could serve as a potential target for new therapy. Our reviewed identifies covalent modifications of HMGB1, and highlighted how these PTMs affect the functions of HMGB1 protein in a variety of cellular and extra cellular processes as well as diseases and therapy.

Keywords: HMGB1; autoimmune disease; cancer; modification; post-translational.

Figure 1

Different HMGB1 redox states: A: The oxidized isoform has all-oxidized cysteine in HMGB1and is seen as noninflammatory; B: The Disulfide isoform has a disulfide bond that induces cytokine cell release; C: The thiol isoform has a reduced cysteine with chemoattractant activity.

Figure 3

Potential HMGB1 receptor and possible signaling pathways. A: HMGB1-RAGE interaction leads to phosphorylation of MAP-kinases p38, p42/p44, and c-jun NH2-terminal kinase, resulting in NF-B activation. B: HMGB1 binds to many membrane molecules such as heparin, proteoglycans including syndecan-1, sulfoglycolipids, and phospholipid and mediate phosphorylated of extracellular regulated kinase-1 and -2. that involves signaling via an unidentified Gi/o protein. C: HMGB1 through RAGE can activate two different cascades, one involving the involves the Ras-mitogen-activated protein (MAP) kinase pathway and a second that involves a small GTPases Rac and Cdc42 leading to cytoskeletal reorganization and subsequent nuclear factor (NF)-B nuclear translocation-mediating inflammation. D: RAGE is also expressed on mononuclear phagocytes where its interaction with AGEs enhances cellular oxidant stress and generation of thiobarbituric acid reactive substances and activation of NF-B. RAGE signaling has also been shown to stimulates an inflammatory response when AGE-modified β2 microglobulin binds RAGE in mononuclear phagocytes to mediate monocyte chemotaxis and induce TNF release.

Figure 2

The role of post-translational modification (PTM) in translocation and immune activation by HMGB1. HMGB1 undergoes PTMs (e.g., acetylation, phosphorylation, methylation, etc.) following cell activation induced by external stimuli (necrotic cell or by active secretion from activated macrophages/monocytes). This modification leads to translocation of HMGB1 from the nucleus into the cytoplasm, into secretory endosomes and out of the cell. Extracellular HMGB1 functions as an immune activator by binding TLRs 2 and 4 and RAGE on immune cells like macrophages and neutrophils. Following binding, it leads to activation of gene expression via NF-kB. This explains the pro-inflammatory role HMGB1 during PTMs.