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 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-x(L), 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.
Hackam
A S
AS
Centre for Molecular Medicine and Therapeutics and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Yassa
A S
AS
Singaraja
R
R
Metzler
M
M
Gutekunst
C A
CA
Gan
L
L
Warby
S
S
Wellington
C L
CL
Vaillancourt
J
J
Chen
N
N
Gervais
F G
FG
Raymond
L
L
Nicholson
D W
DW
Hayden
M R
MR
D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects*; D002352:Carrier Proteins / Q000737:chemistry / Q000633:toxicity*; D020169:Caspases / Q000502:physiology*; D002460:Cell Line; D004268:DNA-Binding Proteins; D006801:Humans; D006816:Huntington Disease / Q000209:etiology*; D008969:Molecular Sequence Data; D010455:Peptides / Q000633:toxicity; D013329:Structure-Activity Relationship; D014162:Transfection
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C073368:HIP1 protein, human; D010455:Peptides; C097188:polyglutamine; D020169:Caspases