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@ARTICLE{Hett:136920,
author = {Hett, Erik C and Slater, Louise H and Mark, Kevin G and
Kawate, Tomohiko and Monks, Brian G and Stutz, Andrea and
Latz, Eicke and Hung, Deborah T},
title = {{C}hemical genetics reveals a kinase-independent role for
protein kinase {R} in pyroptosis.},
journal = {Nature chemical biology},
volume = {9},
number = {6},
issn = {1552-4450},
address = {Basingstoke},
publisher = {Nature Publishing Group},
reportid = {DZNE-2020-03242},
pages = {398-405},
year = {2013},
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.},
keywords = {Animals / Bacillus anthracis: enzymology / Caspase 1:
metabolism / Catalytic Domain / Cell Death / Cell Line /
Enzyme-Linked Immunosorbent Assay / HSP90 Heat-Shock
Proteins: metabolism / Hydrogen-Ion Concentration /
Inflammation / Macrophages: metabolism / Mice / Mice, Inbred
BALB C / Models, Biological / Peptide Hydrolases: metabolism
/ Proteasome Endopeptidase Complex: metabolism / Protein
Conformation / eIF-2 Kinase: chemistry / HSP90 Heat-Shock
Proteins (NLM Chemicals) / eIF-2 Kinase (NLM Chemicals) /
Peptide Hydrolases (NLM Chemicals) / Caspase 1 (NLM
Chemicals) / Proteasome Endopeptidase Complex (NLM
Chemicals)},
cin = {AG Latz},
ddc = {570},
cid = {I:(DE-2719)1013024},
pnm = {342 - Disease Mechanisms and Model Systems (POF3-342)},
pid = {G:(DE-HGF)POF3-342},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:23603659},
pmc = {pmc:PMC6615456},
doi = {10.1038/nchembio.1236},
url = {https://pub.dzne.de/record/136920},
}