%0 Journal Article
%A Hett, Erik C
%A Slater, Louise H
%A Mark, Kevin G
%A Kawate, Tomohiko
%A Monks, Brian G
%A Stutz, Andrea
%A Latz, Eicke
%A Hung, Deborah T
%T Chemical genetics reveals a kinase-independent role for protein kinase R in pyroptosis.
%J Nature chemical biology
%V 9
%N 6
%@ 1552-4450
%C Basingstoke
%I Nature Publishing Group
%M DZNE-2020-03242
%P 398-405
%D 2013
%X Formation of the inflammasome, a scaffolding complex that activates caspase-1, is important in numerous diseases. Pyroptotic cell death induced by anthrax lethal toxin (LT) is a model for inflammasome-mediated caspase-1 activation. We discovered 7-desacetoxy-6,7-dehydrogedunin (7DG) in a phenotypic screen as a small molecule that protects macrophages from LT-induced death. Using chemical proteomics, we identified protein kinase R (PKR) as the target of 7DG and show that RNAi knockdown of PKR phenocopies treatment with 7DG. Further, we show that PKR's role in ASC assembly and caspase-1 activation induced by several different inflammasome stimuli is independent of PKR's kinase activity, demonstrating that PKR has a previously uncharacterized role in caspase-1 activation and pyroptosis that is distinct from its reported kinase-dependent roles in apoptosis and inflammasome formation in lipopolysaccharide-primed cells. Remarkably, PKR has different roles in two distinct cell death pathways and has a broad role in inflammasome function relevant in other diseases.
%K Animals
%K Bacillus anthracis: enzymology
%K Caspase 1: metabolism
%K Catalytic Domain
%K Cell Death
%K Cell Line
%K Enzyme-Linked Immunosorbent Assay
%K HSP90 Heat-Shock Proteins: metabolism
%K Hydrogen-Ion Concentration
%K Inflammation
%K Macrophages: metabolism
%K Mice
%K Mice, Inbred BALB C
%K Models, Biological
%K Peptide Hydrolases: metabolism
%K Proteasome Endopeptidase Complex: metabolism
%K Protein Conformation
%K eIF-2 Kinase: chemistry
%K HSP90 Heat-Shock Proteins (NLM Chemicals)
%K eIF-2 Kinase (NLM Chemicals)
%K Peptide Hydrolases (NLM Chemicals)
%K Caspase 1 (NLM Chemicals)
%K Proteasome Endopeptidase Complex (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:23603659
%2 pmc:PMC6615456
%R 10.1038/nchembio.1236
%U https://pub.dzne.de/record/136920