Chaperone-like Activity of High-Mobility Group Box 1 Protein and Its Role in Reducing the Formation of Polyglutamine Aggregates

Abstract

High-mobility group box 1 protein (HMGB1), which mainly exists in the nucleus, has recently been shown to function as a sentinel molecule for viral nucleic acid sensing and an autophagy regulator in the cytoplasm. In this study, we studied the chaperone-like activity of HMGB1 and 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 cytoplasmic luciferase activity as a reporter protein in hamster lung fibroblast O23 cells with expression of HMGB1. Next, we demonstrated that HMGB1 inhibited the formation of aggregates and toxicity caused by expanded polyglutamine (polyQ), one of the main causes of Huntington disease. HMGB1 directly interacted with polyQ on immunofluorescence and coimmunoprecipitation assay, whereas the overexpression of HMGB1 or exogenous administration of recombinant HMGB1 protein remarkably reduced polyQ aggregates in SHSY5Y cells and hmgb1−/− mouse embryonic fibroblasts upon filter trap and immunofluorescence assay. Finally, overexpressed HMGB1 proteins in mouse embryonic primary striatal neurons also bound to polyQ and decreased the formation of polyQ aggregates. To this end, we have demonstrated that HMGB1 exhibits chaperone-like activity and a possible therapeutic candidate in polyQ disease.

HMGB1 is involved in autophagy inhibition caused by SNCA/α-synuclein overexpression

“…Notably, a new study has identified HMGB1 as a chaperone-like molecule, which interacts with polyglutamine (polyQ) and reduces aggregation and toxicity of polyQ, the pathogenic cause of Huntington disease. 29 The finding, together with the previous report that HMGB1 interacts with SNCA filaments in PD brain samples, 21 revealed a possible connection between HMGB1 and the pathogenic protein aggregates associated with neurodegenerative diseases including PD and Huntington disease. Meanwhile, SNCA and polyQ have been shown to impair autophagy, without a fully understood mechanism.…”

HMGB1 in health and disease

“…HMGB1-mediated autophagy increases chemoresistance in cancer cells, including colon cancer, pancreatic cancer, osteosarcoma, leukemia, gastric cancer, and ovarian cancer (Huang et al, 2012a; Kang et al, 2010; Liu et al, 2011c; Livesey et al, 2012b; Yang et al, 2012e; Zhan et al, 2012; Zhang et al, 2012d; Zhao et al, 2011a). In addition, HMGB1-mediated autophagy in vitro and/or in vivo prevents polyglutamine aggregates in Huntington’s disease (Min et al, 2013), systemic inflammation during sepsis (Hagiwara et al, 2012; Yanai et al, 2013), N-methyl-D-aspartate-induced excitotoxicity (Perez-Carrion and Cena, 2013), hepatic ischemia-reperfusion injury (Fang et al, 2013b; Shen et al, 2013), and sustains T cell survival in myositis (Zong et al, 2014). Conditional knockdown of HMGB1 in the liver or heart cannot change baseline autophagy level and mitochondrial quality (Huebener et al, 2014).…”

Resveratrol Reduces the Proinflammatory Effects and Lipopolysaccharide- Induced Expression of HMGB1 and TLR4 in RAW264.7 Cells

“…S33025, Molecular Probes, Invitrogen) and the cells were washed three times with PBS. The cover slips were mounted on glass slides with mounting medium [29] and observed using a confocal microscope (Olympus Inc., Center Valley, PA, USA). The integrated optical density (IOD) of every imaged RAW264.7 cell was determined using the Image-Pro Plus 5.0 software (Media Cybernetics, Inc., Bethesda, MD, USA).…”