Inositol hexakisphosphate kinases promote autophagy

Eiichiro Nagata, Adolfo Saiardi, Hideo Tsukamoto, Tadayuki Satoh, Yoshiko Itoh, Johbu Itoh, Mamoru Shibata, Shunya Takizawa, Shigeharu Takagi

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

We and other authors have previously reported that increasing cellular diphosphoinositol pentakisphosphate (InsP7) levels increases cell sensitivity to cell death. In the present study, we elucidated the relationship between inositol hexakisphosphate kinases (InsP6Ks), which form InsP7, and autophagy using InsP6Ks overexpression and disruption systems. A large number of autophagosomes were induced in cells transfected with InsP6Ks, as revealed by the conversion of LC3-I to LC3-II, which was examined using immunoblotting, immunocytochemistry, and immuno-electron microscopy for LC3; consequently, the rate of cell death was higher among these cells than among cells transfected with a control vector, as shown using propidium iodide staining. However, the reduction of InsP6Ks levels using RNAi suppressed the formation of autophagosomes. Moreover, the number of autophagosomes and the rate of cell death were significantly higher among cells transfected with InsP6Ks subjected to staurosporine-induced stress than among cells transfected with InsP6Ks subjected to normal conditions. The cell death induced by InsP6Ks was not completely suppressed by z-VAD-fmk, a pan-caspase inhibitor. The phosphorylation of mammalian target of rapamycin (mTOR) was also depressed in cells overexpressing InsP6Ks, suggesting that the mTOR pathway regulates autophagosomes generated by InsP6Ks. These findings imply that InsP6Ks promote autophagy and induce caspase-independent cell death. This phenomenon opens a new pathway of autophagy via InsP6Ks.

Original languageEnglish
Pages (from-to)2065-2071
Number of pages7
JournalInternational Journal of Biochemistry and Cell Biology
Volume42
Issue number12
DOIs
Publication statusPublished - 2010 Dec 1

Keywords

  • Autophagy
  • Caspase-independent cell death
  • Inositol hexakisphosphate kinases
  • Inositol pyrophosphate
  • MTOR/PIP

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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