The proinflammatory protein HMGB1 is a substrate of transglutaminase-2 and forms high-molecular weight complexes with autoantigens

Abstract

High-mobility group box 1 (HMGB1) is a chromatin-associated protein that, in response to stress or injury, translocates from the nucleus to the extracellular milieu, where it functions as an alarmin. HMGB1's function is in part determined by the complexes (HMGB1c) it forms with other molecules. However, structural modifications in the HMGB1 polypeptide that may regulate HMGB1c formation have not been previously described. In this report, we observed high-molecular weight, denaturing-resistant HMGB1c in the plasma and peripheral blood mononuclear cells of individuals with systemic lupus erythematosus (SLE) and, to a much lesser extent, in healthy subjects. Differential HMGB1c levels were also detected in mouse tissues and cultured cells, in which these complexes were induced by endotoxin or the immunological adjuvant alum. Of note, we found that HMGB1c formation is catalyzed by the protein-cross-linking enzyme transglutaminase-2 (TG2). Cross-link site mapping and MS analysis revealed that HMGB1 can be cross-linked to TG2 as well as a number of additional proteins, including human autoantigens. These findings have significant functional implications for studies of cellular stress responses and innate immunity in SLE and other autoimmune disease.

HMGB1 protein as a novel target for cancer

“…Secretory HMGB1 protein molecules have an ability to bind with Toll like receptors (TLRs) present on immune cells and with RAGE (Receptor for advanced glycation end products) expressed on cancer cells [5]. HMGB1 has been reported to work as damage associated molecular pattern (DAMP) as well as in the progression of inflammatory and autoimmune diseases [6,7]. To explicate the sundry role of HMGB1, in current review, we would be elaborating the various structural forms to be targeted by drugs to mitigate the genesis of inflammatory diseases particularly different types of cancers and its different clinical and biological aspects.

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Identification of hepatic protein-protein interaction targets for betaine homocysteine S-methyltransferase

“…Additionally, HHcy due to liver injury or stress concurs with inflammation, a context in which transglutaminases are activated, thus promoting crosslinking and production of high-Mr complexes that may include i.e. the proinflammatory protein HMGB1 [ 78 ], in turn translocated to the cytoplasm [ 36 ]. BHMT is also a substrate of transglutaminase [ 33 , 51 ], but whether this modification takes place in HHcy remains unknown.…”

Transglutaminase 2 Up-Regulation Is Associated with Inflammatory Response in PBMC from Healthy Subjects with Hypovitaminosis D

“…Recently, we demonstrated the up-regulation of some inflammatory markers, such as TNF-α, IL-6, and high mobility group box 1 (HMGB1), and at the same time the increase of TG2 mRNA levels; in human periodontal ligament cells obtained from patients with chronic periodontitis, compared with healthy subjects [22]. Interestingly, high-molecular weight and denaturing-resistant HMGB1 complexes, rising from protein-cross-linking activity of TG2 enzyme, have been observed in the plasma and PBMC of individuals with immune disorders and, to a much lesser extent, in healthy subjects [23].…”