TY  - JOUR
AU  - Hett, Erik C
AU  - Slater, Louise H
AU  - Mark, Kevin G
AU  - Kawate, Tomohiko
AU  - Monks, Brian G
AU  - Stutz, Andrea
AU  - Latz, Eicke
AU  - Hung, Deborah T
TI  - Chemical genetics reveals a kinase-independent role for protein kinase R in pyroptosis.
JO  - Nature chemical biology
VL  - 9
IS  - 6
SN  - 1552-4450
CY  - Basingstoke
PB  - Nature Publishing Group
M1  - DZNE-2020-03242
SP  - 398-405
PY  - 2013
AB  - 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.
KW  - Animals
KW  - Bacillus anthracis: enzymology
KW  - Caspase 1: metabolism
KW  - Catalytic Domain
KW  - Cell Death
KW  - Cell Line
KW  - Enzyme-Linked Immunosorbent Assay
KW  - HSP90 Heat-Shock Proteins: metabolism
KW  - Hydrogen-Ion Concentration
KW  - Inflammation
KW  - Macrophages: metabolism
KW  - Mice
KW  - Mice, Inbred BALB C
KW  - Models, Biological
KW  - Peptide Hydrolases: metabolism
KW  - Proteasome Endopeptidase Complex: metabolism
KW  - Protein Conformation
KW  - eIF-2 Kinase: chemistry
KW  - HSP90 Heat-Shock Proteins (NLM Chemicals)
KW  - eIF-2 Kinase (NLM Chemicals)
KW  - Peptide Hydrolases (NLM Chemicals)
KW  - Caspase 1 (NLM Chemicals)
KW  - Proteasome Endopeptidase Complex (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:23603659
C2  - pmc:PMC6615456
DO  - DOI:10.1038/nchembio.1236
UR  - https://pub.dzne.de/record/136920
ER  -