A novel caspase-2 complex containing TRAF2 and RIP1.
The enzymatic activity of caspases is implicated in the execution of apoptosis and inflammation. Here we demonstrate a novel nonenzymatic function for caspase-2 other than its reported proteolytic role in apoptosis. Caspase-2, unlike caspase-3, -6, -7, -9, -11, -12, and -14, is a potent inducer of NF-kappaB and p38 MAPK activation in a TRAF2-mediated way. Caspase-2 interacts with TRAF1, TRAF2, and RIP1. Furthermore, we demonstrate that endogenous caspase-2 is recruited into a large and inducible protein complex, together with TRAF2 and RIP1. Structure-function analysis shows that NF-kappaB activation occurs independent of enzymatic activity of the protease and that the caspase recruitment domain of caspase-2 is sufficient for the activation of NF-kappaB and p38 MAPK. These results demonstrate the inducible assembly of a novel protein complex consisting of caspase-2, TRAF2, and RIP1 that activates NF-kappaB and p38 MAPK through the caspase recruitment domain of caspase-2 independently of its proteolytic activity.
Lamkanfi
Mohamed
M
Unit of Molecular Signalling and Cell Death, Department for Molecular Biomedical Research, Ghent University and Flemish Interuniversity Institute for Biotechnology, Technologiepark 927, Zwijnaarde B-9052, Belgium.
D'hondt
Kathleen
K
Vande Walle
Lieselotte
L
van Gurp
Marjan
M
Denecker
Geertrui
G
Demeulemeester
Jill
J
Kalai
Michael
M
Declercq
Wim
W
Saelens
Xavier
X
Vandenabeele
Peter
P
D000818:Animals; D053143:Caspase 2; D020169:Caspases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D046912:Multiprotein Complexes; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism; D017434:Protein Structure, Tertiary; D047990:TNF Receptor-Associated Factor 1 / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism*; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D020690:GTPase-Activating Proteins; D046912:Multiprotein Complexes; D016328:NF-kappa B; C490620:Ralbp1 protein, mouse; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D048051:p38 Mitogen-Activated Protein Kinases; D053143:Caspase 2; D020169:Caspases