Caspase-1 activates nuclear factor of the kappa-enhancer in B cells independently of its enzymatic activity.

Abstract

The proteolytic activity of caspases is involved in apoptosis and inflammation. In this regard, caspase-1 is required for pro-interleukin (IL)-1beta and pro-IL-18 maturation. We report here on a novel function of caspase-1 as an activator of nuclear factor of the kappa-enhancer in B-cells (NF-kappaB) and p38 mitogen-activated protein kinase (MAPK). This function is not shared by the murine caspase-1 homologues caspase-11 and -12. In contrast to pro-IL-1beta maturation, caspase-1-induced NF-kappaB activation is not inhibited by the virus-derived caspase-1 inhibitor cytokine response modifier A and is equally induced by the enzymatically inactive caspase-1 C285A mutant. Although the general NF-kappaB-inhibiting protein A20 inhibits caspase-1-derived activation of NF-kappaB, dominant-negative forms of TRAF2 and RIP1 have no effect. We demonstrate that caspase-1 interacts with RIP2 and that dominant-negative forms of RIP2 and IkappaB kinase complex-beta inhibit caspase-1-mediated NF-kappaB activation. Structure-function analysis shows that the caspase recruitment domain of caspase-1 mediates the activation of NF-kappaB and p38 MAPK. These data demonstrate that caspase-1 contributes to inflammation by two distinct pathways: proteolysis of pro-IL-1beta, and RIP2-dependent activation of NF-kappaB and p38 MAPK mediated by the caspase recruitment domain.

• Authors: Mohamed Lamkanfi, Michael Kalai, Xavier Saelens, Wim Declercq, Peter Vandenabeele
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 279 Issue 23 Pg. 24785-93 (Jun 04 2004) ISSN: 0021-9258 [Print] United States
• PMID: 15039421 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AGFG1 protein, human
• DNA, Complementary
• I kappa B beta protein
• I-kappa B Proteins
• Interleukin-1
• NF-kappa B
• Nuclear Pore Complex Proteins
• Proteins
• RNA-Binding Proteins
• TNF Receptor-Associated Factor 2
• Luciferases
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• CASP12 protein, human
• Casp12 protein, mouse
• Casp4 protein, mouse
• Caspase 12
• Caspases
• Caspases, Initiator
• Caspase 1

Topics

• Animals
• Apoptosis
• B-Lymphocytes (metabolism)
• Caspase 1 (metabolism)
• Caspase 12
• Caspases (metabolism)
• Caspases, Initiator
• Cell Line
• Cloning, Molecular
• DNA, Complementary (metabolism)
• Dose-Response Relationship, Drug
• Enzyme Activation
• Genes, Dominant
• Humans
• I-kappa B Proteins (metabolism)
• Immunoblotting
• Interleukin-1 (metabolism)
• Luciferases (metabolism)
• MAP Kinase Signaling System
• Mice
• Mitogen-Activated Protein Kinases (metabolism)
• Models, Biological
• Mutation
• NF-kappa B (metabolism)
• Nuclear Pore Complex Proteins (metabolism)
• Plasmids (metabolism)
• Precipitin Tests
• Proteins (metabolism)
• RNA-Binding Proteins (metabolism)
• Signal Transduction
• Structure-Activity Relationship
• TNF Receptor-Associated Factor 2
• Time Factors
• Transfection
• p38 Mitogen-Activated Protein Kinases