JAK/STAT1 signaling promotes HMGB1 hyperacetylation and nuclear translocation.
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.
The Elmezzi Graduate School of Molecular Medicine, North Shore-LIJ Health System, Manhasset, NY 11030.
Ben
B
Lu
Daniel J
DJ
Antoine
Kevin
K
Kwan
Peter
P
Lundbäck
Heidi
H
Wähämaa
Hanna
H
Schierbeck
Melissa
M
Robinson
Marieke A D
MA
Van Zoelen
Huan
H
Yang
Jianhua
J
Li
Helena
H
Erlandsson-Harris
Sangeeta S
SS
Chavan
Haichao
H
Wang
Ulf
U
Andersson
Kevin J
KJ
Tracey
D000107:Acetylation; D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism*; D002853:Chromatography, Liquid; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli; D024243:HMGB1 Protein / Q000378:metabolism*; D007150:Immunohistochemistry; D007370:Interferon Type I / Q000494:pharmacology; D053613:Janus Kinase 1 / Q000378:metabolism*; D008070:Lipopolysaccharides; D051379:Mice; D011728:Pyridones / Q000494:pharmacology; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D053719:Tandem Mass Spectrometry
C524063:2-tert-butyl-9-fluoro-3,6-dihydro-7H-benz(h)imidazo(4,5-f)isoquinoline-7-one; D001562:Benzimidazoles; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D007370:Interferon Type I; D008070:Lipopolysaccharides; D011728:Pyridones; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1
cytokine; damage-associated molecular pattern; innate immunity; pathogen-associated molecular pattern; therapy