HIPPI–HIP1 – a deadly duo

Abstract

Huntington's disease is a neurodegenerative disorder characterized by a polyglutamine expansion at the N-terminus of the huntingtin protein (HTT) that leads to selective loss of neurons in the striatum by a hitherto unknown apoptotic mechanism. A molecular basis for the strong correlation between polyglutamine expansion of HTT and subsequent neurodegeneration has, until now, eluded scientists. The implication that caspase-8, a death effector domain (DED)-containing cysteine protease responsible for the initiation of receptor-mediated apoptosis, is required for this process raises the possibility that DEDs might facilitate the assembly of a death complex that engages a novel caspase-8-dependent cell death pathway.In an attempt to unravel the molecular basis of HTT-mediated cytotoxicity, several HTT-interacting proteins have been identified. One such protein, named HIP1 (HTT-interacting protein 1), contains a pseudo DED-like motif (pDED), reminiscent of the DED motif found in pro-caspase-8. Furthermore, HIP1 is pro-apoptotic and induces cell death in a pDED-dependent manner by activation of caspases.Although HIP1 and HTT colocalize in mammalian cells, the affinity of HTT for HIP1 decreases significantly as the polyglutamine tract in HTT expands. Consequently, a current model of Huntington's disease is that an expanded polyglutamine tract in HTT might result in the release of HIP1 protein and subsequent induction of a novel apoptotic pathway.To explore this possibility, Gervais and colleagues [1xRecruitment and activation of caspase-8 by the Huntingtin-interacting protein Hip-1 and a novel partner Hippi. Gervais, F.G et al. Nat. Cell Biol. 2002; 4: 95–105Crossref | PubMed | Scopus (208)See all References][1] employed a yeast two-hybrid screen using the pDED of Hip-1 as bait. This strategy yielded HIPPI (HIP1 protein interactor), a novel partner for HIP1 that contains a pDED domain strikingly similar to that present in HIP1. More importantly, Gervais et al. show that HIPPI is a molecular accomplice of HIP1, which results in recruitment and activation of procaspase-8 by the HIPPI–HIP1 complex. This HIPPI–HIP-1 interaction could therefore act as the initiating event in a non-receptor-mediated pathway for the activation of caspase-8 and subsequent cell death. The identification of this new apoptotic pathway that is dependent on the extent of polyglutamine expansion in HTT, goes some way to providing a molecular basis for the pathogenesis of Huntington's disease and could provide novel targets for inhibiting the selective neuronal loss associated with this disease.