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

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.

Increased apoptosis, huntingtin inclusions and altered differentiation in muscle cell cultures from Huntington's disease subjects

“…Coherently with previous reports indicating a role of caspase-8 and -9 in HD, 22,26,27 we herein describe activation of these two proteases in HD myoblasts (Figure 6c). Both caspase initiators may contribute to the pathogenic cascade of events leading to caspase-3 activation and finally to apoptosis.…”

Direct activation of caspase 8 by the proapoptotic E2 protein of HPV18 independent of adaptor proteins

“…12,16,21 Only few adaptors for caspase 8 activation have been described so far, and they all contain DED or pseudo-DEDs. 10,22 We showed here that the E2 protein directly binds to the DEDs of caspase 8, not involving a 'death fold domain,' as the motif of E2 required for this interaction could be restricted to 27 amino acids. Caspase 8 co-expression with E2 greatly stimulates filaments formation, suggesting that caspase 8 plays an active role in filament assembly rather than being recruited to pre-existing E2 filaments.…”

Bifunctional apoptosis inhibitor (BAR) protects neurons from diverse cell death pathways

“…HIP1 and Hippi reportedly form a complex together with pro-Caspase-8, thereby triggering caspase activation and cell death. 10 In addition, Bap31 is a transmembrane protein that resides mainly in the ER and which also contains a pseudo-DED. 22 Similar to BAR, Bap31 reportedly binds Bcl-2 as well as proCaspase-8.…”

“…8,9 Further, neuronal death in Huntington's disease may involve Caspase-8 activation dependent on a protein complex comprising HIP1, Hippi, and Caspase-8. 10 The bifunctional apoptosis inhibitor (BAR) is a multidomain protein that was first discovered as an inhibitor of Bax-induced cell death. 11 BAR is capable of inhibiting apoptosis induced by TNF-family death receptors ('extrinsic pathway') as well as mitochondria-dependent apoptosis ('intrinsic pathway').…”