JAK/STAT1 signaling promotes HMGB1 hyperacetylation and nuclear translocation

被引：309

作者：

Lu, Ben ^{[1
,2
]}

Antoine, Daniel J. ^{[3
]}

Kwan, Kevin ^{[2
]}

Lundback, Peter ^{[4
]}

Wahamaa, Heidi ^{[4
]}

Schierbeck, Hanna ^{[4
]}

Robinson, Melissa ^{[2
]}

Van Zoelen, Marieke A. D. ^{[2
]}

Yang, Huan ^{[2
]}

Li, Jianhua ^{[2
]}

Erlandsson-Harris, Helena ^{[4
]}

Chavan, Sangeeta S. ^{[2
]}

Wang, Haichao ^{[5
]}

Andersson, Ulf ^{[4
]}

Tracey, Kevin J. ^{[1
,2
,4
]}

机构：

[1] North Shore LIJ Hlth Syst, Elmezzi Grad Sch Mol Med, Manhasset, NY 11030 USA

[2] Feinstein Inst Med Res, Lab Biomed Sci, Manhasset, NY 11030 USA

[3] Univ Liverpool, Ctr Drug Safety Sci, MRC, Dept Mol & Clin Pharmacol, Liverpool L69 3GE, Merseyside, England

[4] Karolinska Inst, Dept Womens & Childrens Hlth, S-17176 Stockholm, Sweden

[5] N Shore Univ Hosp, Dept Emergency Med, Manhasset, NY 11030 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2014年 / 111卷 / 08期

基金：

美国国家卫生研究院;

关键词：

damage-associated molecular pattern; cytokine; pathogen-associated molecular pattern; innate immunity; therapy; MOBILITY GROUP BOX-1; INFLAMMASOME ACTIVATION; STERILE INFLAMMATION; NLRP3; INFLAMMASOME; IMMUNE-RESPONSES; CYTOKINE RELEASE; GENE-EXPRESSION; PROTEIN HMGB1; RECEPTOR; CELLS;

D O I：

10.1073/pnas.1316925111

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：3068 / 3073

页数：6

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