JAK/STAT1 signaling promotes HMGB1 hyperacetylation and nuclear translocation

Ben Lu, Daniel J Antoine, Kevin Kwan, Peter Lundbäck, Heidi Wähämaa, Hanna Schierbeck, Melissa Robinson, Marieke A D Van Zoelen, Huan Yang, Jianhua Li, Helena Erlandsson-Harris, Sangeeta S Chavan, Haichao Wang, Ulf Andersson, Kevin J Tracey

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)3068-73
Number of pages6
JournalProceedings of the National Academy of Sciences
Issue number8
Publication statusPublished - 25 Feb 2014


  • Acetylation
  • Active Transport, Cell Nucleus
  • Analysis of Variance
  • Animals
  • Benzimidazoles
  • Blotting, Western
  • Cell Nucleus
  • Chromatography, Liquid
  • Enzyme-Linked Immunosorbent Assay
  • Escherichia coli
  • HMGB1 Protein
  • Immunohistochemistry
  • Interferon Type I
  • Janus Kinase 1
  • Lipopolysaccharides
  • Mice
  • Pyridones
  • STAT1 Transcription Factor
  • Signal Transduction
  • Tandem Mass Spectrometry
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


Dive into the research topics of 'JAK/STAT1 signaling promotes HMGB1 hyperacetylation and nuclear translocation'. Together they form a unique fingerprint.

Cite this