Caspase-1 activates nuclear factor of the kappa-enhancer in B cells independently of its enzymatic activity.
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.
Lamkanfi
Mohamed
M
Unit of Molecular Signalling and Cell Death, Department for Molecular Biomedical Research, Flanders Interuniversity Institute of Biotechnology, Ghent University, B-9052 Zwijnaarde, Belgium.
Kalai
Michael
M
Saelens
Xavier
X
Declercq
Wim
W
Vandenabeele
Peter
P
D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism*; D053454:Caspase 12; D020169:Caspases / Q000378:metabolism; D053471:Caspases, Initiator; D002460:Cell Line; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005799:Genes, Dominant; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D015151:Immunoblotting; D007375:Interleukin-1 / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011506:Proteins / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D047992:TNF Receptor-Associated Factor 2; D013997:Time Factors; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
C119724:AGFG1 protein, human; D018076:DNA, Complementary; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D007375:Interleukin-1; D016328:NF-kappa B; D028861:Nuclear Pore Complex Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; D047992:TNF Receptor-Associated Factor 2; D008156:Luciferases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C506444:CASP12 protein, human; C506440:Casp12 protein, mouse; C101136:Casp4 protein, mouse; D053454:Caspase 12; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1