Article abstract
Nature Cell Biology 4, 95 - 105 (2002)
Published online: 14 January 2002 | doi:10.1038/ncb735
Recruitment and activation of caspase-8 by the Huntingtin-interacting protein Hip-1 and a novel partner Hippi
François G. Gervais1, Roshni Singaraja2, Steven Xanthoudakis1, Claire-Anne Gutekunst3, Blair R. Leavitt2, Martina Metzler2, Abigail S. Hackam2,4, John Tam1, John P. Vaillancourt1, Vicky Houtzager1, Dita M. Rasper1, Sophie Roy1, Michael R. Hayden2 & Donald W. Nicholson1
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.
- Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Pointe-Claire-Dorval, Quebec, Canada H9R 4P8
- Centre for Molecular Medicine and Therapeutics, and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4
- Department of Neurology, Emory University, Atlanta, Georgia 30322, USA
- Current address: Department of Ophthalmology, Wilmer Eye Institute, John Hopkins School of Medicine, Baltimore, Maryland 21287, USA
Correspondence to: Donald W. Nicholson1 e-mail: donald_nicholson@merck.com
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