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

• Published in: Cell Vol. 129; no. 1; pp. 45 - 56
• Main Authors: Bruey, Jean-Marie, Bruey-Sedano, Nathalie, Luciano, Frederic, Zhai, Dayong, Balpai, Ruchi, Xu, Chunyan, Kress, Christina L, Bailly-Maitre, Beatrice, Li, Xiaoqing, Osterman, Andrei, Matsuzawa, Shu-ichi, Terskikh, Alexey V, Faustin, Benjamin, Reed, John C
• Format: Journal Article
• Language: English
• Published: United States 06.04.2007
• Subjects: Acetylmuramyl-Alanyl-Isoglutamine - pharmacology; Adaptor Proteins, Signal Transducing - metabolism; Animals; Apoptosis; Apoptosis Regulatory Proteins - metabolism; bcl-X Protein - metabolism; Bone Marrow Cells; Caspase 1 - metabolism; Cell Line; Enzyme Activation; HeLa Cells; Humans; Inflammation - enzymology; Interleukin-1beta - metabolism; Macrophages - cytology; Macrophages - metabolism; Mice; Mice, Knockout; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism
• ISSN: 0092-8674
• DOI: 10.1016/j.cell.2007.01.045

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.