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 language | English |
|---|---|
| Pages (from-to) | 41299-41308 |
| Number of pages | 10 |
| Journal | Journal of Biological Chemistry |
| Volume | 275 |
| Issue number | 52 |
| DOIs | |
| State | Published - Dec 29 2000 |
| Externally published | Yes |
Fingerprint
ASJC Scopus subject areas
- Biochemistry
Cite this
Huntingtin interacting protein 1 induces apoptosis via a novel caspase-dependent death effector domain. / Hackam, Abigail S; Yassa, Ayman S.; Singaraja, Roshni; Metzler, Martina; Gutekunst, Claire Anne; Gan, Lu; Warby, Simon; Wellington, Cheryl L.; Vaillancourt, John; Chen, Nansheng; Gervais, Francois G.; Raymond, Lynn; Nicholson, Donald W.; Hayden, Michael R.
In: Journal of Biological Chemistry, Vol. 275, No. 52, 29.12.2000, p. 41299-41308.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Huntingtin interacting protein 1 induces apoptosis via a novel caspase-dependent death effector domain
AU - Hackam, Abigail S
AU - Yassa, Ayman S.
AU - Singaraja, Roshni
AU - Metzler, Martina
AU - Gutekunst, Claire Anne
AU - Gan, Lu
AU - Warby, Simon
AU - Wellington, Cheryl L.
AU - Vaillancourt, John
AU - Chen, Nansheng
AU - Gervais, Francois G.
AU - Raymond, Lynn
AU - Nicholson, Donald W.
AU - Hayden, Michael R.
PY - 2000/12/29
Y1 - 2000/12/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0034731370&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034731370&partnerID=8YFLogxK
U2 - 10.1074/jbc.M008408200
DO - 10.1074/jbc.M008408200
M3 - Article
C2 - 11007801
AN - SCOPUS:0034731370
VL - 275
SP - 41299
EP - 41308
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 52
ER -