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Recruitment and activation of caspase-8 by the Huntingtin-interacting protein Hip-1 and a novel partner Hippi

Nature Cell Biology volume 4, pages 95–105 (2002)Cite this article

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.

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Figure 1: Organization of Hippi and Hip-1.
Figure 2: Distribution of Hippi mRNA and Hip-1 and Hippi protein in brain and other tissues.
Figure 3: Expression of Hippi in mouse brain.
Figure 4: Subcellular colocalization of endogenous Hip-1 and Hippi in human neuronal NT2 cells.
Figure 5: Structural requirements for interaction of Hip-1 and Hippi.
Figure 6: Interaction of Hippi and Hip-1 in cells.
Figure 7: The length of the Htt polyglutamine stretch governs the availability of Hip-1 to bind to Hippi.
Figure 8: Hippi increases Hip-1-mediated toxicity in cells.
Figure 9: Hip-1 and Hippi associate with caspase-8 and are dependent on it to mediate cellular toxicity.
Figure 10: Proposed model for Hippi/Hip-1 mediated apoptosis.

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Acknowledgements

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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  1. Abigail S. Hackam

    Present address: Department of Ophthalmology, Wilmer Eye Institute, John Hopkins School of Medicine, Baltimore, Maryland, 21287, USA

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Pointe-Claire-Dorval, Quebec, H9R 4P8, Canada

    François G. Gervais, Steven Xanthoudakis, John Tam, John P. Vaillancourt, Vicky Houtzager, Dita M. Rasper, Sophie Roy & Donald W. Nicholson

  2. Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, V5Z 4H4, British Columbia, Canada

    Roshni Singaraja, Blair R. Leavitt, Martina Metzler, Abigail S. Hackam & Michael R. Hayden

  3. Department of Neurology, Emory University, Atlanta, 30322, Georgia, USA

    Claire-Anne Gutekunst

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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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