Bcl-2 and Bcl-XL Regulate Proinflammatory Caspase-1 Activation by Interaction with NALP1

Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Cell (Impact Factor: 32.24). 05/2007; 129(1):45-56. DOI: 10.1016/j.cell.2007.01.045
Source: PubMed


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.

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    • "Activation of P2X7R by LPS and ATP results in MyD88-dependent NFκB activation (signal 2), and transcription of pro-IL-1β [11]. Following LPS priming of monocytes, P2X7R activation stimulates NADPH oxidase generation of superoxide anions, thereby facilitating NLRP3 activation [12]. "
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    PLoS ONE 03/2013; 8(3):e58733. DOI:10.1371/journal.pone.0058733 · 3.23 Impact Factor
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    • "Furthermore, Bcl-2 and Bcl-xL bind and suppress NLR-family protein NALP1, a nucleotide-dependent activator of cytokine-processing protease caspase-1, to inhibit caspase-1 activation and IL-1β production [19]. Bcl-2-deficient macrophages exhibit more caspase-1 processing and IL-1β production, whereas Bcl-2-overexpressing macrophages implicate less caspase-1 processing and IL-1β production [19]. These findings imply an important role of Bcl-2 family in the regulation of three types of programmed cell death. "
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    PLoS ONE 10/2012; 7(10):e47299. DOI:10.1371/journal.pone.0047299 · 3.23 Impact Factor
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