A chemical probe for Protein Kinase R (PKR) that protects against toxin-induced death of macrophages - as seen in response to anthrax, for example - is reported this week in Nature Chemical Biology. The work reveals a new role for PKR in cell death pathways, which is independent of its enzymatic function.

Lethal toxin, produced by Bacillus anthracis, the causative agent of anthrax, disrupts numerous host functions to kill host immune cells called macrophages. The death of these infected macrophages protects the host from infection so understanding the underlying mechanisms that promote cell death is important.

Erik Hett, Deborah Hung and colleagues perform a high-throughput chemical screen to identify a small molecule that suppresses lethal toxin-induced death. The authors identify PKR as the target of their small molecule, and show that PKR promotes a form of cell death called pyroptosis independent of its kinase activity, which expands our understanding of the PKR in inflammatory response beyond its known kinase-dependent activity in promoting macrophage cell death by apoptosis.