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000136920 0247_ $$2doi$$a10.1038/nchembio.1236
000136920 0247_ $$2pmid$$apmid:23603659
000136920 0247_ $$2pmc$$apmc:PMC6615456
000136920 0247_ $$2ISSN$$a1552-4450
000136920 0247_ $$2ISSN$$a1552-4469
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000136920 037__ $$aDZNE-2020-03242
000136920 041__ $$aEnglish
000136920 082__ $$a570
000136920 1001_ $$0P:(DE-HGF)0$$aHett, Erik C$$b0$$eCorresponding author
000136920 245__ $$aChemical genetics reveals a kinase-independent role for protein kinase R in pyroptosis.
000136920 260__ $$aBasingstoke$$bNature Publishing Group$$c2013
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000136920 264_1 $$2Crossref$$3print$$bSpringer Science and Business Media LLC$$c2013-06-01
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000136920 520__ $$aFormation 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.
000136920 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
000136920 542__ $$2Crossref$$i2013-04-21$$uhttp://www.springer.com/tdm
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000136920 650_7 $$2NLM Chemicals$$aHSP90 Heat-Shock Proteins
000136920 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aeIF-2 Kinase
000136920 650_7 $$0EC 3.4.-$$2NLM Chemicals$$aPeptide Hydrolases
000136920 650_7 $$0EC 3.4.22.36$$2NLM Chemicals$$aCaspase 1
000136920 650_7 $$0EC 3.4.25.1$$2NLM Chemicals$$aProteasome Endopeptidase Complex
000136920 650_2 $$2MeSH$$aAnimals
000136920 650_2 $$2MeSH$$aBacillus anthracis: enzymology
000136920 650_2 $$2MeSH$$aCaspase 1: metabolism
000136920 650_2 $$2MeSH$$aCatalytic Domain
000136920 650_2 $$2MeSH$$aCell Death
000136920 650_2 $$2MeSH$$aCell Line
000136920 650_2 $$2MeSH$$aEnzyme-Linked Immunosorbent Assay
000136920 650_2 $$2MeSH$$aHSP90 Heat-Shock Proteins: metabolism
000136920 650_2 $$2MeSH$$aHydrogen-Ion Concentration
000136920 650_2 $$2MeSH$$aInflammation
000136920 650_2 $$2MeSH$$aMacrophages: metabolism
000136920 650_2 $$2MeSH$$aMice
000136920 650_2 $$2MeSH$$aMice, Inbred BALB C
000136920 650_2 $$2MeSH$$aModels, Biological
000136920 650_2 $$2MeSH$$aPeptide Hydrolases: metabolism
000136920 650_2 $$2MeSH$$aProteasome Endopeptidase Complex: metabolism
000136920 650_2 $$2MeSH$$aProtein Conformation
000136920 650_2 $$2MeSH$$aeIF-2 Kinase: chemistry
000136920 7001_ $$0P:(DE-HGF)0$$aSlater, Louise H$$b1
000136920 7001_ $$0P:(DE-HGF)0$$aMark, Kevin G$$b2
000136920 7001_ $$0P:(DE-HGF)0$$aKawate, Tomohiko$$b3
000136920 7001_ $$0P:(DE-HGF)0$$aMonks, Brian G$$b4
000136920 7001_ $$0P:(DE-HGF)0$$aStutz, Andrea$$b5
000136920 7001_ $$0P:(DE-2719)2000062$$aLatz, Eicke$$b6$$udzne
000136920 7001_ $$0P:(DE-HGF)0$$aHung, Deborah T$$b7
000136920 77318 $$2Crossref$$3journal-article$$a10.1038/nchembio.1236$$b : Springer Science and Business Media LLC, 2013-04-21$$n6$$p398-405$$tNature Chemical Biology$$v9$$x1552-4450$$y2013
000136920 773__ $$0PERI:(DE-600)2190276-8$$a10.1038/nchembio.1236$$gVol. 9, no. 6, p. 398 - 405$$n6$$p398-405$$q9:6<398 - 405$$tNature chemical biology$$v9$$x1552-4450$$y2013
000136920 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615456
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000136920 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2000062$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b6$$kDZNE
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