title: RIP and FADD: two "death domain"-containing proteins can induce apoptosis by convergent, but dissociable, pathways.
abstract: With use of the yeast two-hybrid system, the proteins RIP and FADD/MORT1 have been shown to interact with the "death domain" of the Fas receptor. Both of these proteins induce apoptosis in mammalian cells. Using receptor fusion constructs, we provide evidence that the self-association of the death domain of RIP by itself is sufficient to elicit apoptosis. However, both the death domain and the adjacent alpha-helical region of RIP are required for the optimal cell killing induced by the overexpression of this gene. By contrast, FADD's ability to induce cell death does not depend on crosslinking. Furthermore, RIP and FADD appear to activate different apoptotic pathways since RIP is able to induce cell death in a cell line that is resistant to the apoptotic effects of Fas, tumor necrosis factor, and FADD. Consistent with this, a dominant negative mutant of FADD, lacking its N-terminal domain, blocks apoptosis induced by RIP but not by FADD. Since both pathways are blocked by CrmA, the interleukin 1 beta converting enzyme family protease inhibitor, these results suggest that FADD and RIP can act along separable pathways that nonetheless converge on a member of the interleukin 1 beta converting enzyme family of cysteine proteases.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: S
authors.initials: S
authors.lastname: Grimm
authors.forename: B Z
authors.initials: BZ
authors.lastname: Stanger
authors.forename: P
authors.initials: P
authors.lastname: Leder
mesh_terms: D017209:Apoptosis; D029681:Arabidopsis Proteins; D020170:Caspase 1; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000502:physiology; D044943:Fatty Acid Desaturases / Q000502:physiology*; D006801:Humans; D010940:Plant Proteins / Q000502:physiology*; D011506:Proteins / Q000502:physiology*; D011940:Receptor Aggregation; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D017384:Sequence Deletion; D015843:Serpins / Q000502:physiology; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D014764:Viral Proteins; D019014:fas Receptor / Q000502:physiology
chemical_list: D029681:Arabidopsis Proteins; D015853:Cysteine Proteinase Inhibitors; D010940:Plant Proteins; D011506:Proteins; D015843:Serpins; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D019014:fas Receptor; C074641:interleukin-1beta-converting enzyme inhibitor; D044943:Fatty Acid Desaturases; C084083:Fad7 protein, Arabidopsis; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D003546:Cysteine Endopeptidases; D020170:Caspase 1