Role of chaperone-like activity of high mobility group box 1 : its role in reducing the formation of polyglutamine aggregates

Abstract

High mobility group box 1 (HMGB1), which mainly exists in the nucleus, can be secreted into extracellular area and functions as a DAMP molecule through TLR 2, 4, and RAGE. Recently, the function of HMGB1 in cytoplasm has been reported as a sentinel molecule for viral nucleic acid sensing and a autophagy regulator. In this study, we aimed at discovering unknown function of cytoplasmic HMGB1 and identified the chaperone-like activity of HMGB1. We found that HMGB1 inhibited the chemically-induced aggregation of insulin and lysozyme, as well as the heat-induced aggregation of citrate synthase. HMGB1 also restored the heat-induced suppression of luciferase activity as a reporter protein in O23 cells after co-transfection of firefly luciferase with HMGB1. Next, we demonstrated that HMGB1 prevented the formation of aggregates and toxicity caused by expanded polyglutamine (polyQ), the main cause of Huntington’s disease. HMGB1 interacted with polyQ in immunofluorescence and co-immunoprecipitation assay, while the overexpression of HMGB1 or exogenous administration of recombinant HMGB1 proteins remarkably reduced polyQ induced aggregates in SHSY5Y cells and hmgb1-deficient mouse embryonic fibroblasts upon filter trap and immunofluorescence assay. Finally, overexpressed HMGB1 proteins in mouse primary embryonic striatal neurons also bound to polyQ and decreased the formation of polyQ aggregates. To this end, we have demonstrated that HMGB1 has chaperone-like activity and suggest the possibility of HMGB1 as a therapeutic agent in polyQ disease.