JAK/STAT1 signaling promotes HMGB1 hyperacetylation and nuclear translocation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 8; pp. 3068 - 3073
• Main Authors: Lu, Ben, Antoine, Daniel J., Kwan, Kevin, Lundbäck, Peter, Wähämaa, Heidi, Schierbeck, Hanna, Robinson, Melissa, Van Zoelen, Marieke A. D., Yang, Huan, Li, Jianhua, Erlandsson-Harris, Helena, Chavan, Sangeeta S., Wang, Haichao, Andersson, Ulf, Tracey, Kevin J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25.02.2014; National Acad Sciences
• Series: From the Cover
• Subjects: Acetylation; Active Transport, Cell Nucleus - drug effects; Active Transport, Cell Nucleus - physiology; Analysis of Variance; Animals; Benzimidazoles - pharmacology; Biological Sciences; Blotting, Western; Cell nucleus; Cell Nucleus - metabolism; Cells; Cellular biology; Chromatography, Liquid; Cytokines; Cytoplasm; Disulfides; Enzyme-Linked Immunosorbent Assay; Escherichia coli; Gene expression regulation; HMGB1 Protein - metabolism; Immunohistochemistry; Inflammation; Interferon Type I - pharmacology; Janus Kinase 1 - metabolism; Lipopolysaccharides; Macrophages; Mass spectrometry; Medicin och hälsovetenskap; Mice; Pathogenesis; Pharmacology; Pyridones - pharmacology; Secretion; Signal Transduction - drug effects; Signal Transduction - physiology; STAT1 Transcription Factor - metabolism; Tandem Mass Spectrometry; cytokine; innate immunity; pathogen-associated molecular pattern; therapy; damage-associated molecular pattern
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1316925111

Extracellular high-mobility group box (HMGB)1 mediates inflammation during sterile and infectious injury and contributes importantly to disease pathogenesis. The first critical step in the release of HMGB1 from activated immune cells is mobilization from the nucleus to the cytoplasm, a process dependent upon hyperacetylation within two HMGB1 nuclear localization sequence (NLS) sites. The inflammasomes mediate the release of cytoplasmic HMGB1 in activated immune cells, but the mechanism of HMGB1 translocation from nucleus to cytoplasm was previously unknown. Here, we show that pharmacological inhibition of JAK/STAT1 inhibits LPS-induced HMGB1 nuclear translocation. Conversely, activation of JAK/STAT1 by type 1 interferon (IFN) stimulation induces HMGB1 translocation from nucleus to cytoplasm. Mass spectrometric analysis unequivocally revealed that pharmacological inhibition of the JAK/STAT1 pathway or genetic deletion of STAT1 abrogated LPS- or type 1 IFN-induced HMGB1 acetylation within the NLS sites. Together, these results identify a critical role of the JAK/STAT1 pathway in mediating HMGB1 cytoplasmic accumulation for subsequent release, suggesting that the JAK/STAT1 pathway is a potential drug target for inhibiting HMGB1 release.