title: A novel caspase-2 complex containing TRAF2 and RIP1.
abstract: 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.
authors.affiliation: 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.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Lamkanfi
authors.forename: Kathleen
authors.initials: K
authors.lastname: D'hondt
authors.forename: Lieselotte
authors.initials: L
authors.lastname: Vande Walle
authors.forename: Marjan
authors.initials: M
authors.lastname: van Gurp
authors.forename: Geertrui
authors.initials: G
authors.lastname: Denecker
authors.forename: Jill
authors.initials: J
authors.lastname: Demeulemeester
authors.forename: Michael
authors.initials: M
authors.lastname: Kalai
authors.forename: Wim
authors.initials: W
authors.lastname: Declercq
authors.forename: Xavier
authors.initials: X
authors.lastname: Saelens
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenabeele
mesh_terms: 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
chemical_list: 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