title: The death domain kinase RIP1 links the immunoregulatory CD40 receptor to apoptotic signaling in carcinomas.
abstract: CD40, a tumor necrosis factor (TNF) receptor family member, is widely recognized for its prominent role in the antitumor immune response. The immunostimulatory effects of CD40 ligation on malignant cells can be switched to apoptosis upon disruption of survival signals transduced by the binding of the adaptor protein TRAF6 to CD40. Apoptosis induction requires a TRAF2-interacting CD40 motif but is initiated within a cytosolic death-inducing signaling complex after mobilization of receptor-bound TRAF2 to the cytoplasm. We demonstrate that receptor-interacting protein 1 (RIP1) is an integral component of this complex and is required for CD40 ligand-induced caspase-8 activation and tumor cell killing. Degradation of the RIP1 K63 ubiquitin ligases cIAP1/2 amplifies the CD40-mediated cytotoxic effect, whereas inhibition of CYLD, a RIP1 K63 deubiquitinating enzyme, reduces it. This two-step mechanism of apoptosis induction expands our appreciation of commonalities in apoptosis regulatory pathways across the TNF receptor superfamily and provides a telling example of how TNF family receptors usurp alternative programs to fulfill distinct cellular functions.
authors.affiliation: Molecular and Cellular Biology Laboratory, Division of Basic Sciences, University of Crete Medical School, 71003 Heraklion, Greece.
authors.forename: Pauline G
authors.initials: PG
authors.lastname: Knox
authors.forename: Clare C
authors.initials: CC
authors.lastname: Davies
authors.forename: Marina
authors.initials: M
authors.lastname: Ioannou
authors.forename: Aristides G
authors.initials: AG
authors.lastname: Eliopoulos
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D023201:CD40 Ligand / Q000378:metabolism*; D002277:Carcinoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006367:HeLa Cells; D006801:Humans; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism
chemical_list: D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D023201:CD40 Ligand; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D053181:Caspase 8