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Nat Chem Biol DOI:10.1038/nchembio.1236

Chemical genetics reveals a kinase-independent role for protein kinase R in pyroptosis.

Publication TypeJournal Article
Year of Publication2013
AuthorsHett, EC, Slater, LH, Mark, KG, Kawate, T, Monks, BG, Stutz, A, Latz, E, Hung, DT
JournalNat Chem Biol
Date Published2013 Jun
KeywordsAnimals, Bacillus anthracis, Caspase 1, Catalytic Domain, Cell Death, Cell Line, eIF-2 Kinase, Enzyme-Linked Immunosorbent Assay, HSP90 Heat-Shock Proteins, Hydrogen-Ion Concentration, Inflammation, Macrophages, Mice, Mice, Inbred BALB C, Models, Biological, Peptide Hydrolases, Proteasome Endopeptidase Complex, Protein Conformation

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.


Alternate JournalNat. Chem. Biol.
PubMed ID23603659
Grant ListF32AI084323 / AI / NIAID NIH HHS / United States
U54 AI057159 / AI / NIAID NIH HHS / United States