Journal Article

DZNE-2020-03242

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Chemical genetics reveals a kinase-independent role for protein kinase R in pyroptosis.

Hett, E. C. (Corresponding author) ; Slater, L. H. ; Mark, K. G. ; Kawate, T. ; Monks, B. G. ; Stutz, A. ; Latz, E.DZNE* ; Hung, D. T.

2013
Nature Publishing Group Basingstoke

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Please use a persistent id in citations: doi:10.1038/nchembio.1236

Abstract: 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.

Keyword(s): Animals (MeSH) ; Bacillus anthracis: enzymology (MeSH) ; Caspase 1: metabolism (MeSH) ; Catalytic Domain (MeSH) ; Cell Death (MeSH) ; Cell Line (MeSH) ; Enzyme-Linked Immunosorbent Assay (MeSH) ; HSP90 Heat-Shock Proteins: metabolism (MeSH) ; Hydrogen-Ion Concentration (MeSH) ; Inflammation (MeSH) ; Macrophages: metabolism (MeSH) ; Mice (MeSH) ; Mice, Inbred BALB C (MeSH) ; Models, Biological (MeSH) ; Peptide Hydrolases: metabolism (MeSH) ; Proteasome Endopeptidase Complex: metabolism (MeSH) ; Protein Conformation (MeSH) ; eIF-2 Kinase: chemistry (MeSH) ; HSP90 Heat-Shock Proteins ; eIF-2 Kinase ; Peptide Hydrolases ; Caspase 1 ; Proteasome Endopeptidase Complex

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Contributing Institute(s):

1. Innate Immunity in Neurodegeneration (AG Latz)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2013

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 10 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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