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.
Highlights
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
We further demonstrated the presence of HMGB1 in large protein complexes in systemic lupus erythematosus (SLE) patients
In standard SDSPAGE followed by Western blot analysis, the plasma levels of the prototypical 29-kDa HMGB1 varied slightly among individual samples, but there were no significant differences observed between SLE patients and healthy controls (Fig. 1A, bottom panels)
Summary
Willis‡§1, Linan Wang§¶, Takuma Tsuzuki Wada‡§, Mark Gardner‡§, Omar Abdouni‡§, Jeffrey Hampton‡§, Giancarlo Valiente‡§, Nicholas Young‡§, Stacy Ardoin‡§, Sudha Agarwalʈ**, Michael A. Freitas§¶, Lai-Chu Wu‡ ‡‡2, and Wael N. Jarjour‡§2,3 From the Departments of ‡Internal Medicine, ¶Cancer Biology and Genetics, and ‡‡Biological Chemistry and Pharmacology and ʈDivision of Biosciences, The Ohio State University College of Dentistry, Columbus, Ohio 43210, the **Department of Orthopedics, The Ohio State University College of Medicine, Columbus, Ohio 43210, and §The Ohio State University Wexner Medical Center, Columbus, Ohio 43210
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