Novel role of PKR in inflammasome activation and HMGB1 release

Ben Lu, Takahisa Nakamura, Karen Inouye, Jianhua Li, Yiting Tang, Peter Lundback, Sergio I. Valdes-Ferrer, Peder S. Olofsson, Thomas Kalb, Jesse Roth, Yongrui Zou, Helena Erlandsson-Harris, Huan Yang, Jenny P. -Y. Ting, Haichao Wang, Ulf Andersson, Daniel J. Antoine, Sangeeta S. Chavan, Goekhan S. Hotamisligil, Kevin J. Tracey*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)670-+
Number of pages6
JournalNature
Volume488
Issue number7413
DOIs
Publication statusPublished - 30 Aug 2012

Keywords

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

Cite this