title: The kinase activity of PKR represses inflammasome activity.
abstract: The protein kinase R (PKR) functions in the antiviral response by controlling protein translation and inflammatory cell signaling pathways. We generated a transgenic, knock-in mouse in which the endogenous PKR is expressed with a point mutation that ablates its kinase activity. This novel animal allows us to probe the kinase-dependent and -independent functions of PKR. We used this animal together with a previously generated transgenic mouse that is ablated for PKR expression to determine the role of PKR in regulating the activity of the cryopyrin inflammasome. Our data demonstrate that, in contradiction to earlier reports, PKR represses cryopyrin inflammasome activity. We demonstrate that this control is mediated through the established function of PKR to inhibit protein translation of constituents of the inflammasome to prevent initial priming during innate immune signaling. These findings identify an important role for PKR to dampen inflammation during the innate immune response and caution against the previously proposed therapeutic strategy to inhibit PKR to treat inflammation.
authors.affiliation: Centre for Cancer Research, Hudson Institute of Medical Research, 27-31 Wright St, Clayton, Victoria 3168, Australia.|Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Howard C H
authors.initials: HC
authors.lastname: Yim
authors.affiliation: Centre for Cancer Research, Hudson Institute of Medical Research, 27-31 Wright St, Clayton, Victoria 3168, Australia.|Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Die
authors.initials: D
authors.lastname: Wang
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 27-31 Wright St, Clayton, Victoria 3168, Australia.|Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Liang
authors.initials: L
authors.lastname: Yu
authors.affiliation: Centre for Cancer Research, Hudson Institute of Medical Research, 27-31 Wright St, Clayton, Victoria 3168, Australia.|Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Christine L
authors.initials: CL
authors.lastname: White
authors.affiliation: Chicago Genomics Facility, University of Chicago, IL 60637, USA.
authors.forename: Pieter W
authors.initials: PW
authors.lastname: Faber
authors.affiliation: Centre for Cancer Research, Hudson Institute of Medical Research, 27-31 Wright St, Clayton, Victoria 3168, Australia.|Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Bryan R G
authors.initials: BR
authors.lastname: Williams
authors.affiliation: Centre for Cancer Research, Hudson Institute of Medical Research, 27-31 Wright St, Clayton, Victoria 3168, Australia.|Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Sadler
mesh_terms: D000818:Animals; D058847:Inflammasomes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020382:Interleukin-18 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D008264:Macrophages / Q000201:enzymology / Q000276:immunology; D008822:Mice, Transgenic; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000096:biosynthesis; D019892:eIF-2 Kinase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D019892:eIF-2 Kinase; C000605978:protein kinase R, mouse