Functional degradation: A mechanism of NLRP1 inflammasome activation by diverse pathogen enzymes

Degradation triggers the alarm Inflammasomes are multiprotein complexes that orchestrate proinflammatory cytokine secretion and cell death. Proteases such as anthrax lethal factor can activate an inflammasome known as NLRP1B, but the mechanism for this activation has been unclear. Chui et al. used genome-wide knockout screens to show that proteolysis of NLRP1B by lethal factor induces proteasomal degradation of the amino-terminal domains of NLRP1B and eventual cell death. Sandstrom et al. found that degradation of the amino-terminal domains of NLRP1B resulted in the release of a carboxyl-terminal fragment that activates caspase-1. This process, called “functional degradation,” allows the immune system to detect pathogen-associated activities, much as it recognizes pathogen-associated antigens. Science , this issue p. 82 , p. eaau1330