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.
Bruey
Jean-Marie
JM
Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Bruey-Sedano
Nathalie
N
Luciano
Frederic
F
Zhai
Dayong
D
Balpai
Ruchi
R
Xu
Chunyan
C
Kress
Christina L
CL
Bailly-Maitre
Beatrice
B
Li
Xiaoqing
X
Osterman
Andrei
A
Matsuzawa
Shu-ichi
S
Terskikh
Alexey V
AV
Faustin
Benjamin
B
Reed
John C
JC
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*
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