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Papers In Press, published online ahead of print September 27, 2000
Centre for Molecular Medicine and Therapeutics, Vancouver, BC V5Z 4H4
Corresponding Author: ahackam{at}cmmt.ubc.ca
Huntington disease (HD) 1 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 pro-apoptotic protein. Over-expression 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 (DED) 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 anti-apoptotic 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 pro-apoptotic mediator, and suggest that HIP-1 may be a molecular accomplice in the pathogenesis of HD.
J. Biol. Chem, 10.1074/jbc.M008408200
Submitted on September 13, 2000
Accepted on September 27, 2000
Huntingtin interacting protein 1 (HIP-1) induces apoptosis via a novel caspase-dependent death effector domain
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