Inositol Hexakisphosphate Kinases Induce Cell Death in Huntington Disease

Yoshiko Itoh,Hideo Tsukamoto,Shigeharu Takagi,Johbu Itoh,Yoshinori Okada,Eiichiro Nagata,Russell L Margolis,Shunya Takizawa,Adolfo Saiardi,Akira Sawa,Tadayuki Satoh

doi:10.1074/jbc.m111.220749

Abstract

Inositol pyrophosphate diphosphoinositol pentakisphosphate is ubiquitously present in mammalian cells and contains highly energetic pyrophosphate bonds. We have previously reported that inositol hexakisphosphate kinase type 2 (InsP(6)K2), which converts inositol hexakisphosphate to inositol pyrophosphate diphosphoinositol pentakisphosphate, mediates apoptotic cell death via its translocation from the nucleus to the cytoplasm. Here, we report that InsP(6)K2 is localized mainly in the cytoplasm of lymphoblast cells from patients with Huntington disease (HD), whereas this enzyme is localized in the nucleus in control lymphoblast cells. The large number of autophagosomes detected in HD lymphoblast cells is consistent with the down-regulation of Akt in response to InsP(6)K2 activation. Consistent with these observations, the overexpression of InsP(6)Ks leads to the depletion of Akt phosphorylation and the induction of cell death. These results suggest that InsP(6)K2 activation is associated with the pathogenesis of HD.

Highlights

Under stress conditions, InsP6K2 strongly induces apoptotic cell death and is translocated from the nucleus to the cytoplasm [5]
InsP6K2 Exists in the Cytoplasm of Huntington disease (HD) Lymphoblast Cells— We recently showed that InsP6Ks, InsP6K2, regulate cell death and promote autophagy [14]
This study provides evidence that InsP6K2, which generates InsP7, promotes cell death in HD, suggesting the primary role of inositol pyrophosphates in HD pathophysiology

Summary

The abbreviations used are

InsP6, inositol hexakisphosphate; InsP7, diphosphoinositol pentakisphosphate; InsP6K, inositol hexakisphosphate kinase; HD, Huntington disease. InsP6Ks were originally purified from rat brain because neuronal tissues possess the highest level of InsP6K activity in mammalian tissues [13]. The mechanism by which inositol pyrophosphates control brain functions and how alterations in InsP7 signals affect neurological disorders remain unclear. We have previously reported that InsP6Ks promote autophagy [14], a cellular clearance mechanism that occurs in patients with Huntington disease (HD). In this study, we investigated whether InsP6K signaling is activated in HD lymphoblast cells. We show that inositol pyrophosphates contribute to the HD lymphoblast cell death process, possibly by promoting apoptotic cell death. We suggest that InsP6Ks, and inositol pyrophosphates, are associated with the pathophysiology of neurodegenerative disorders

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION