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

Cell. 2007 Apr 6;129(1):45-56. doi: 10.1016/j.cell.2007.01.045.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylmuramyl-Alanyl-Isoglutamine / pharmacology
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins / 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*
  • bcl-X Protein / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • BCL2L1 protein, human
  • Interleukin-1beta
  • NLRP1 protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-X Protein
  • Acetylmuramyl-Alanyl-Isoglutamine
  • Caspase 1