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 journalArticle

20 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

Fingerprint

Autophagy
Cell death
Cell Death
Sirolimus
Phosphorylation
Caspase Inhibitors
Staurosporine
Propidium
Caspases
Electron microscopy
Immunoelectron Microscopy
RNA Interference
inositol hexakisphosphate kinase
Immunoblotting
Immunohistochemistry
Staining and Labeling
Autophagosomes
inositol heptakisphosphate

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

Cite this

Nagata, E., Saiardi, A., Tsukamoto, H., Satoh, T., Itoh, Y., Itoh, J., ... Takagi, S. (2010). Inositol hexakisphosphate kinases promote autophagy. International Journal of Biochemistry and Cell Biology, 42(12), 2065-2071. https://doi.org/10.1016/j.biocel.2010.09.013

Inositol hexakisphosphate kinases promote autophagy. / Nagata, Eiichiro; Saiardi, Adolfo; Tsukamoto, Hideo; Satoh, Tadayuki; Itoh, Yoshiko; Itoh, Johbu; Shibata, Mamoru; Takizawa, Shunya; Takagi, Shigeharu.

In: International Journal of Biochemistry and Cell Biology, Vol. 42, No. 12, 12.2010, p. 2065-2071.

Research output: Contribution to journalArticle

Nagata, E, Saiardi, A, Tsukamoto, H, Satoh, T, Itoh, Y, Itoh, J, Shibata, M, Takizawa, S & Takagi, S 2010, 'Inositol hexakisphosphate kinases promote autophagy', International Journal of Biochemistry and Cell Biology, vol. 42, no. 12, pp. 2065-2071. https://doi.org/10.1016/j.biocel.2010.09.013
Nagata, Eiichiro ; Saiardi, Adolfo ; Tsukamoto, Hideo ; Satoh, Tadayuki ; Itoh, Yoshiko ; Itoh, Johbu ; Shibata, Mamoru ; Takizawa, Shunya ; Takagi, Shigeharu. / Inositol hexakisphosphate kinases promote autophagy. In: International Journal of Biochemistry and Cell Biology. 2010 ; Vol. 42, No. 12. pp. 2065-2071.
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