title: Bcl-2 and Bcl-XL regulate proinflammatory caspase-1 activation by interaction with NALP1.
abstract: 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.
authors.affiliation: Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Bruey
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bruey-Sedano
authors.forename: Frederic
authors.initials: F
authors.lastname: Luciano
authors.forename: Dayong
authors.initials: D
authors.lastname: Zhai
authors.forename: Ruchi
authors.initials: R
authors.lastname: Balpai
authors.forename: Chunyan
authors.initials: C
authors.lastname: Xu
authors.forename: Christina L
authors.initials: CL
authors.lastname: Kress
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bailly-Maitre
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Li
authors.forename: Andrei
authors.initials: A
authors.lastname: Osterman
authors.forename: Shu-ichi
authors.initials: S
authors.lastname: Matsuzawa
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Terskikh
authors.forename: Benjamin
authors.initials: B
authors.lastname: Faustin
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001854:Bone Marrow Cells; D020170:Caspase 1 / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000201:enzymology; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000070576:NLR Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; D053583:Interleukin-1beta; D000070576:NLR Proteins; C427903:NLRP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D020170:Caspase 1