Novel role of PKR in inflammasome activation and HMGB1 release

被引：628

作者：

Lu, Ben ^{[1
,2
]}

Nakamura, Takahisa ^{[3
]}

Inouye, Karen ^{[3
]}

Li, Jianhua ^{[1
]}

Tang, Yiting ^{[4
]}

Lundback, Peter ^{[5
]}

Valdes-Ferrer, Sergio I. ^{[1
,2
]}

Olofsson, Peder S. ^{[1
]}

Kalb, Thomas ^{[1
]}

Roth, Jesse ^{[1
]}

Zou, Yongrui ^{[4
]}

Erlandsson-Harris, Helena ^{[5
]}

Yang, Huan ^{[1
]}

Ting, Jenny P. -Y. ^{[6
]}

Wang, Haichao ^{[7
]}

Andersson, Ulf

Antoine, Daniel J. ^{[8
]}

Chavan, Sangeeta S. ^{[1
]}

Hotamisligil, Goekhan S. ^{[3
]}

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

机构：

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

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

[3] Harvard Univ, Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA

[4] Feinstein Inst Med Res, Ctr Autoimmun & Musculoskeletal Dis, New York, NY 11030 USA

[5] Karolinska Univ Hosp, Karolinska Inst, Dept Med, S-17176 Stockholm, Sweden

[6] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA

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

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

来源：

NATURE | 2012年 / 488卷 / 7413期

基金：

美国国家卫生研究院;

关键词：

PROTEIN-KINASE PKR; SUBSTRATE RECOGNITION; NLRP3; INFLAMMASOME; APOPTOSIS; ACID; ELF2-ALPHA; INFECTION; PATHWAYS; BINDING; STRESS;

D O I：

10.1038/nature11290

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：

The inflammasome regulates the release of caspase activation-dependent cytokines, including interleukin (IL)-1 beta, IL-18 and high-mobility group box 1 (HMGB1)(1-5). By studying HMGB1 release mechanisms, here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. Exposure of macrophages to inflammasome agonists induced PKR autophosphorylation. PKR inactivation by genetic deletion or pharmacological inhibition severely impaired inflammasome activation in response to double-stranded RNA, ATP, monosodium urate, adjuvant aluminium, rotenone, live Escherichia coli, anthrax lethal toxin, DNA transfection and Salmonella typhimurium infection. PKR deficiency significantly inhibited the secretion of IL-1 beta, IL-18 and HMGB1 in E. coli-induced peritonitis. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. PKR autophosphorylation in a cell-free system with recombinant NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC, also known as PYCARD) and pro-caspase-1 reconstitutes inflammasome activity. These results show a crucial role for PKR in inflammasome activation, and indicate that it should be possible to pharmacologically target this molecule to treat inflammation.

引用

页码：670 / +

页数：6

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