Huntingtin interacting protein 1 induces apoptosis via a novel caspase-dependent death effector domain

Abigail S Hackam, Ayman S. Yassa, Roshni Singaraja, Martina Metzler, Claire Anne Gutekunst, Lu Gan, Simon Warby, Cheryl L. Wellington, John Vaillancourt, Nansheng Chen, Francois G. Gervais, Lynn Raymond, Donald W. Nicholson, Michael R. Hayden

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102 Scopus citations

Abstract

Huntington disease is a devastating neurodegenerative disease caused by the expansion of a polymorphic glutamine tract in huntingtin. The huntingtin interacting protein (HIP-1) was identified by its altered interaction with mutant huntingtin. However, the function of HIP-1 was not known. In this study, we identify HIP-1 as a proapoptotic protein. Overexpression of HIP-1 resulted in rapid caspase 3-dependent cell death. Bioinformatics analyses identified a novel domain in HIP-1 with homology to death effector domains (DEDs) present in proteins involved in apoptosis. Expression of the HIP-1 DED alone resulted in cell death indistinguishable from HIP-1, indicating that the DED is responsible for HIP-1 toxicity. Furthermore, substitution of a conserved hydrophobic phenylalanine residue within the HIP-1 DED at position 398 eliminated HIP-1 toxicity entirely. HIP-1 activity was found to be independent of the DED-containing caspase 8 but was significantly inhibited by the antiapoptotic protein Bcl-xL, implicating the intrinsic pathway of apoptosis in HIP-1-induced cell death. Coexpression of a normal huntingtin fragment capable of binding HIP-1 significantly reduced cell death. Our data identify HIP-1 as a novel proapoptotic mediator and suggest that HIP-1 may be a molecular accomplice in the pathogenesis of Huntington disease.

Original languageEnglish
Pages (from-to)41299-41308
Number of pages10
JournalJournal of Biological Chemistry
Volume275
Issue number52
DOIs
StatePublished - Dec 29 2000
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry

Cite this

Hackam, A. S., Yassa, A. S., Singaraja, R., Metzler, M., Gutekunst, C. A., Gan, L., Warby, S., Wellington, C. L., Vaillancourt, J., Chen, N., Gervais, F. G., Raymond, L., Nicholson, D. W., & Hayden, M. R. (2000). Huntingtin interacting protein 1 induces apoptosis via a novel caspase-dependent death effector domain. Journal of Biological Chemistry, 275(52), 41299-41308. https://doi.org/10.1074/jbc.M008408200