Bcl-2 and Bcl-XL regulate proinflammatory 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 nucleotide-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-1beta (IL-1beta) production. When exposed to MDP, Bcl-2-deficient macrophages exhibit more Caspase-1 processing and IL-1beta production, whereas Bcl-2-overexpressing macrophages demonstrate less Caspase-1 processing and IL-1beta production. The findings reveal an interaction of host defense and Apoptosis machinery.