Huntingtin interacting protein-1 (Hip1) is known to be associated with the N-terminal domain of huntingtin. Although Hip1 can induce apoptosis, the exact upstream signal transduction pathways have not been clarified yet. In the present study, we examined whether activation of intrinsic and/or extrinsic apoptotic pathways occurs during Hip1-mediated neuronal cell death. Overexpression of Hip1 induced cell death through caspase-3 activation in immortalized hippocampal neuroprogenitor cells. Interestingly, proteolytic processing of Hip1 into partial fragments was observed in response to Hip1 transfection and apoptosis-inducing drugs. Moreover, Hip1 was found to directly bind to and activate caspase-9. This promoted cytosolic release of cytochrome c and apoptosis-inducing factor via mitochondrial membrane perturbation. Furthermore, Hip1 could directly bind to Apaf-1, suggesting that the neurotoxic signals of Hip1 transmit through the intrinsic mitochondrial apoptotic pathways and the formation of apoptosome complex.
Bibliographical noteFunding Information:
The authors thank M.R. Hayden for plasmids and antiserum, and S.R. Paik, J. Kim, and M.R. Rosner for their helpful discussions and technical assistance. This study was supported by a grant from the Brain Research Center of the 21st Century Frontier Research Program funded by the Ministry of Science and Technology of Republic of Korea (M103KV010002-03K2201-00600 to K.C.C.), by Basic Science Research Grant from the Korea Research Foundation (KRF2003-015-C00527 to K.C.C.), by a grant from the Korea Health 21 R & D Project, Ministry of Health & Welfare, Republic of Korea (A050181 to K.C.C.), and by Basic Research Grant from the Korea Science and Engineering Foundation (R01-2004-000-10673-0 to K.C.C.). It was also partly supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD) (KRF-2004-005-E00017 to K.C.C).
All Science Journal Classification (ASJC) codes
- Structural Biology
- Molecular Biology
- Cell Biology