Recruitment and activation of caspase-8 by the Huntingtin-interacting protein Hip-1 and a novel partner Hippi

François G Gervais; Roshni Singaraja; Steven Xanthoudakis; Claire-Anne Gutekunst; Blair R Leavitt; Martina Metzler; Abigail S Hackam; John Tam; John P Vaillancourt; Vicky Houtzager; Dita M Rasper; Sophie Roy; Michael R Hayden; Donald W Nicholson

doi:10.1038/ncb735

Recruitment and activation of caspase-8 by the Huntingtin-interacting protein Hip-1 and a novel partner Hippi

Nat Cell Biol. 2002 Feb;4(2):95-105. doi: 10.1038/ncb735.

Authors

François G Gervais¹, Roshni Singaraja, Steven Xanthoudakis, Claire-Anne Gutekunst, Blair R Leavitt, Martina Metzler, Abigail S Hackam, John Tam, John P Vaillancourt, Vicky Houtzager, Dita M Rasper, Sophie Roy, Michael R Hayden, Donald W Nicholson

Affiliation

¹ Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Pointe-Claire-Dorval, Quebec, Canada H9R 4P8.

PMID: 11788820
DOI: 10.1038/ncb735

Abstract

In Huntington disease, polyglutamine expansion of the protein huntingtin (Htt) leads to selective neurodegenerative loss of medium spiny neurons throughout the striatum by an unknown apoptotic mechanism. Binding of Hip-1, a protein normally associated with Htt, is reduced by polyglutamine expansion. Free Hip-1 binds to a hitherto unknown polypeptide, Hippi (Hip-1 protein interactor), which has partial sequence homology to Hip-1 and similar tissue and subcellular distribution. The availability of free Hip-1 is modulated by polyglutamine length within Htt, with disease-associated polyglutamine expansion favouring the formation of pro-apoptotic Hippi-Hip-1 heterodimers. This heterodimer can recruit procaspase-8 into a complex of Hippi, Hip-1 and procaspase-8, and launch apoptosis through components of the 'extrinsic' cell-death pathway. We propose that Htt polyglutamine expansion liberates Hip-1 so that it can form a caspase-8 recruitment complex with Hippi. This novel non-receptor-mediated pathway for activating caspase-8 might contribute to neuronal death in Huntington disease.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Amino Acid Sequence
Animals
Apoptosis / physiology
Carrier Proteins / genetics
Carrier Proteins / metabolism*
Caspase 8
Caspase 9
Caspases / genetics
Caspases / metabolism*
Cells, Cultured
DNA-Binding Proteins*
Enzyme Activation
Humans
Huntingtin Protein
Huntington Disease / enzymology
Huntington Disease / metabolism*
Mice
Models, Molecular
Molecular Sequence Data
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism
Neurons / metabolism*
Neurons / ultrastructure
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Protein Structure, Tertiary
Rats
Sequence Alignment
Tissue Distribution
Two-Hybrid System Techniques

Substances

Adaptor Proteins, Signal Transducing
Carrier Proteins
DNA-Binding Proteins
Esrrbl1 protein, mouse
HIP1 protein, human
HTT protein, human
Hip1 protein, mouse
Htt protein, mouse
Htt protein, rat
Huntingtin Protein
IFT57 protein, human
Nerve Tissue Proteins
Nuclear Proteins
CASP8 protein, human
CASP9 protein, human
Casp8 protein, mouse
Casp8 protein, rat
Casp9 protein, mouse
Casp9 protein, rat
Caspase 8
Caspase 9
Caspases