Huntington's Disease

Pseudo Death Effector Domains Can Still be Deadly

Science's STKE  12 Feb 2002:
Vol. 2002, Issue 119, pp. tw64
DOI: 10.1126/stke.2002.119.tw64

Huntington's disease is associated with the polyglutamine expansion in the NH2-terminus of the Huntingtin protein (Htt), which ultimately results in the apoptotic death of neurons that have accumulated this polyglutamine-expanded form of Htt. Htt interacts with Htt-interacting protein 1 (Hip-1), which has a partially conserved death effector domain [pseudo death effector domain (pDED)]. Polyglutamine expansion of Htt disrupts the Hip-1 interaction. DEDs mediate protein-protein interactions that are involved in apoptosis typically initiated through activation of plasma membrane receptors. A yeast two-hybrid screen identified a second pDED-containing protein that interacted with Hip-1, called Hip-1 protein interactor (Hippi), and one site of interaction was their pDED domains. Gervais et al. also demonstrated that Hippi is expressed, but not restricted to, the brain (in the same regions where Htt is expressed) and that the protein appeared to be localized to the Golgi region. The Hip-1-Hippi interaction was decreased in cells transfected with normal Htt and was promoted by cells transfected with polyglutamine-expanded Htt. Coexpression of Hip-1 and Hippi resulted in increased apoptosis compared with apoptosis induced by expression of Hip-1 or Hippi alone in HEK293T cells or in transfected primary striatal neurons. Procaspase 8 (a mediator of apoptosis), Hip-1, and Hippi were coprecipitated from neuronal NT2 cells or cotransfected HeLa cells. Hippi-Hip-1-induced apoptosis was inhibited by treatments that block caspase 8-dependent apoptosis. Thus, the release of Hip-1 from polyglutamine-expanded Htt may promote the formation of the Hip-1-Hippi complex, which in turn recruits and activates caspase 8, leading to apoptosis.

F. G. Gervais, T. Singaraja, S. Xanthoudakis, C.-A. Gutekuns, B. R. Leavitt, M. Metzler, A. S. Hackam, J. Tam, J .P Vaillancourt, V. Houtzager, D. M. Rasper, S. Roy, M. R. Hayden, D. W. Nicholson, Recruitment and activation of caspase-8 by the Huntintin-interacting protein Hip-1 and a novel partner Hippi. Nature Cell Biol. 4, 95-105 (2002). [Online Journal]