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Originally published In Press as doi:10.1074/jbc.M008408200 on September 27, 2000

J. Biol. Chem., Vol. 275, Issue 52, 41299-41308, December 29, 2000
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Huntingtin Interacting Protein 1 Induces Apoptosis via a Novel Caspase-dependent Death Effector Domain*

Abigail S. Hackamab, Ayman S. Yassaa, Roshni Singarajaa, Martina Metzlerac, Claire-Anne Gutekunstde, Lu Gana, Simon Warbya, Cheryl L. Wellingtonaf, John Vaillancourtg, Nansheng Chenhi, Francois G. Gervaisg, Lynn Raymondhj, Donald W. Nicholsong, and Michael R. Haydenajk

From the a Centre for Molecular Medicine and Therapeutics and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada, V5Z 4H4, d Emory University School of Medicine, Atlanta, Georgia 30322, g Merck Frosst Centre for Therapeutic Research, Montreal, Quebec H9R 4P8, Canada, and the h Department of Psychiatry and Division of Neuroscience, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada

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. Co-expression 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.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

b Supported by a Medical Research Council of Canada postdoctoral fellowship.

c Supported by the Huntington Disease Society of America.

e Supported by the Huntington Disease Society of America and National Science Foundation Grant NS35255.

f Supported by a Hereditary Disease Foundation postdoctoral fellowship.

i Supported by a fellowship from the Huntington Disease Society of America.

j Supported by the Medical Research Council of Canada.

k Supported by the Canadian Network Centers of Excellence (Genetics) and the Medical Research Council of Canada. Established Investigator of the British Columbia Children's Hospital. To whom correspondence should be addressed: Center for Molecular Medicine and Therapeutics, 980 W. 28th Ave., Vancouver, British Columbia V5Z 4H4, Canada. Tel.: 604-875-3535; Fax: 604-875-3819; E-mail: mrh@cmmt.ubc.ca.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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