J Biol Chem. 2004 Jun 4;279(23):24785-93. Epub 2004 Mar 23.

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

Lamkanfi, M., Kalai, M., Saelens, X., Declercq, W., Vandenabeele, P.,
--- - Unit of Molecular Signalling and Cell Death, Department for Molecular Biomedical Research, Flanders Interuniversity Institute of Biotechnology, Ghent University, B-9052 Zwijnaarde, Belgium.
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.
PMID: 15039421External
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
In vivo interaction
  Endogenous
expression
Overexpression DD1 DD2 Reference
Family DD1 DD2 Method Species Region Species Region
CARD Caspase1 Link RIPK2 Co-immunoprecipitation HEK293 Human 2-540 Murine Not specified 15039421
CARD Caspase1 Link RIPK2 Co-immunoprecipitation HEK293 Human 431-540 Murine Not specified 15039421
(Link: click this icon to show interactions only between the two corresponding DDs)
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
Functional Role
Family DD1 DD2 Method Death-related Death-unrelated Reference
CARD Caspase1 Link RIPK2 Reporter gene assay NF-kB activation 15039421
(Link: click this icon to show interactions only between the two corresponding DDs)