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

Huntington disease is a devastating neurodegenerative disease caused by the expansion of a polymorphic glutamine tract in huntingtin. The huntingtin i nteracting protein (HIP-1) was identified by its altered interaction with m utant huntingtin, However, the function of HIP-1 was not known. In this stu dy, we identify HIP-I as a proapoptotic protein. Overexpression of HIP-1 re sulted in rapid caspase 5-dependent cell death. Bioinformatics analyses ide ntified a novel domain in HIP-1 with homology to death effector domains (DE Ds) 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 c onserved hydrophobic phenylalanine residue within the HIP-1 DED at position 398 eliminated HIP-1 toxicity entirely. HIP-1 activity was found to be ind ependent of the DED-containing caspase 8 but was significantly inhibited by the antiapoptotic protein Bcl-x(L), implicating the intrinsic pathway of a poptosis in HIP-1-induced cell death. Coexpression of a normal huntingtin f ragment 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.