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

Nat Chem Biol
Authors
Keywords
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.

Year of Publication
2013
Journal
Nat Chem Biol
Volume
9
Issue
6
Pages
398-405
Date Published
2013 Jun
ISSN
1552-4469
URL
DOI
10.1038/nchembio.1236
PubMed ID
23603659
Links
Grant list
F32AI084323 / AI / NIAID NIH HHS / United States
U54 AI057159 / AI / NIAID NIH HHS / United States