TY - JOUR
T1 - Novel role of PKR in inflammasome activation and HMGB1 release
AU - Lu, Ben
AU - Nakamura, Takahisa
AU - Inouye, Karen
AU - Li, Jianhua
AU - Tang, Yiting
AU - Lundbäck, Peter
AU - Valdes-Ferrer, Sergio I.
AU - Olofsson, Peder S.
AU - Kalb, Thomas
AU - Roth, Jesse
AU - Zou, Yongrui
AU - Erlandsson-Harris, Helena
AU - Yang, Huan
AU - Ting, Jenny P.Y.
AU - Wang, Haichao
AU - Andersson, Ulf
AU - Antoine, Daniel J.
AU - Chavan, Sangeeta S.
AU - Hotamisligil, Gökhan S.
AU - Tracey, Kevin J.
PY - 2012/8/30
Y1 - 2012/8/30
N2 - The inflammasome regulates the release of caspase activation-dependent cytokines, including interleukin (IL)-1Î 2, IL-18 and high-mobility group box 1 (HMGB1). 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-1β, 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.
AB - The inflammasome regulates the release of caspase activation-dependent cytokines, including interleukin (IL)-1Î 2, IL-18 and high-mobility group box 1 (HMGB1). 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-1β, 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.
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U2 - 10.1038/nature11290
DO - 10.1038/nature11290
M3 - Article
C2 - 22801494
AN - SCOPUS:84865511926
VL - 488
SP - 670
EP - 674
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7413
ER -