Bcl-2 and Bcl-XL regulate proinf lammatory caspase-1 activation by interaction with NALP1

Caspases are intracellular proteases that cleave substrates involved in apoptosis or inflammation. In C. elegans, a paradigm for caspase regulation exists in which caspase CED-3 is activated by In ucleotide-binding protein CED-4, which is suppressed by Bcl-2-family protein CED-9. We have identified a mammalian analog of this caspase-regulatory system in the NLR-family protein NALP1, a nucleotide-dependent activator of cytokine-processing protease caspase-1, which responds to bacterial ligand muramyl-dipeptide (MDP). Antiapoptotic proteins Bcl-2 and Bcl-X-L bind and suppress NALP1, reducing caspase-1 activation and interleukin-1 beta (IL-1 beta) production. When exposed to MDP, Bcl-2-deficient macrophages exhibit more caspase-1 processing and IL-1 beta production, whereas Bcl-2-overexpressing macrophages demonstrate less caspase-1 processing and IL-1 beta production. The findings reveal an interaction of host defense and apoptosis machinery.