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.
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We thank G. Shore for the kind gift of the dominant-negative caspase-8 mutant as well as Y.-Z. Yang for help in the generation of the Hip-1 monoclonal antibody and H. Yi for help with electron microscopy. This work was supported by grants to M.R.H. from the Canadian Institutes of Health Research (CIHR), the Huntington Disease Society of America (HDSA) and the Hereditory Disease Foundation (HDF).
Correspondence and requests for materials should be addressed to D.W.N.
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Gervais, F., Singaraja, R., Xanthoudakis, S. et al. Recruitment and activation of caspase-8 by the Huntingtin-interacting protein Hip-1 and a novel partner Hippi. Nat Cell Biol 4, 95–105 (2002). https://doi.org/10.1038/ncb735
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