title: Recruitment and activation of caspase-8 by the Huntingtin-interacting protein Hip-1 and a novel partner Hippi.
abstract: In Huntington disease, polyglutamine expansion of the protein huntingtin (Htt) leads to selective neurodegenerative loss of medium spiny neurons throughout the striatum by an unknown apoptotic mechanism. Binding of Hip-1, a protein normally associated with Htt, is reduced by polyglutamine expansion. Free Hip-1 binds to a hitherto unknown polypeptide, Hippi (Hip-1 protein interactor), which has partial sequence homology to Hip-1 and similar tissue and subcellular distribution. The availability of free Hip-1 is modulated by polyglutamine length within Htt, with disease-associated polyglutamine expansion favouring the formation of pro-apoptotic Hippi-Hip-1 heterodimers. This heterodimer can recruit procaspase-8 into a complex of Hippi, Hip-1 and procaspase-8, and launch apoptosis through components of the 'extrinsic' cell-death pathway. We propose that Htt polyglutamine expansion liberates Hip-1 so that it can form a caspase-8 recruitment complex with Hippi. This novel non-receptor-mediated pathway for activating caspase-8 might contribute to neuronal death in Huntington disease.
authors.affiliation: Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Pointe-Claire-Dorval, Quebec, Canada H9R 4P8.
authors.forename: François G
authors.initials: FG
authors.lastname: Gervais
authors.forename: Roshni
authors.initials: R
authors.lastname: Singaraja
authors.forename: Steven
authors.initials: S
authors.lastname: Xanthoudakis
authors.forename: Claire-Anne
authors.initials: CA
authors.lastname: Gutekunst
authors.forename: Blair R
authors.initials: BR
authors.lastname: Leavitt
authors.forename: Martina
authors.initials: M
authors.lastname: Metzler
authors.forename: Abigail S
authors.initials: AS
authors.lastname: Hackam
authors.forename: John
authors.initials: J
authors.lastname: Tam
authors.forename: John P
authors.initials: JP
authors.lastname: Vaillancourt
authors.forename: Vicky
authors.initials: V
authors.lastname: Houtzager
authors.forename: Dita M
authors.initials: DM
authors.lastname: Rasper
authors.forename: Sophie
authors.initials: S
authors.lastname: Roy
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Donald W
authors.initials: DW
authors.lastname: Nicholson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D016415:Sequence Alignment; D014018:Tissue Distribution; D020798:Two-Hybrid System Techniques
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C449279:Esrrbl1 protein, mouse; C073368:HIP1 protein, human; C086055:HTT protein, human; C489536:Hip1 protein, mouse; C506812:Htt protein, mouse; C499524:Htt protein, rat; D000071058:Huntingtin Protein; C499179:IFT57 protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505526:Casp8 protein, mouse; C505528:Casp8 protein, rat; C506434:Casp9 protein, mouse; C506435:Casp9 protein, rat; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases