Department of Microbiology, Yonsei University College of Medicine, Seoul 120-752, Korea.
J Immunol. 2013 Feb 15;190(4):1797-806. doi: 10.4049/jimmunol.1202472. Epub 2013 Jan 9.
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.
高迁移率族蛋白 B1（HMGB1）主要存在于细胞核内，最近被证明在细胞质中作为病毒核酸感应的哨兵分子和自噬调节剂发挥作用。在本研究中，我们研究了 HMGB1 的伴侣样活性，发现 HMGB1 抑制了胰岛素和溶菌酶的化学诱导聚集，以及柠檬酸合酶的热诱导聚集。HMGB1 还恢复了热诱导的细胞质荧光素酶活性的抑制，作为表达 HMGB1 的仓鼠肺成纤维细胞 O23 中的报告蛋白。接下来，我们证明 HMGB1 抑制了亨廷顿病的主要病因之一——扩张的多聚谷氨酰胺（polyQ）引起的聚集体形成和毒性。HMGB1 在免疫荧光和共免疫沉淀实验中直接与 polyQ 相互作用，而过表达 HMGB1 或外源性给予重组 HMGB1 蛋白，可显著减少 SHSY5Y 细胞和 hmgb1(-/-) 鼠胚胎成纤维细胞中的 polyQ 聚集体，滤过陷阱和免疫荧光实验也证明了这一点。最后，在鼠胚胎纹状体原代神经元中过表达的 HMGB1 蛋白也与 polyQ 结合，并减少了 polyQ 聚集体的形成。为此，我们已经证明 HMGB1 具有伴侣样活性，并且可能是 polyQ 疾病的一种治疗候选物。
