Inositol hexakisphosphate kinase 1 regulates neutrophil function in innate immunity by inhibiting phosphatidylinositol-(3,4,5)-trisphosphate signaling

Amit Prasad, Yonghui Jia, Anutosh Chakraborty, Yitang Li, Supriya K. Jain, Jia Zhong, Saurabh Ghosh Roy, Fabien Loison, Subhanjan Mondal, Jiro Sakai, Catlyn Blanchard, Solomon H. Snyder, Hongbo R. Luo

Research output: Contribution to journalArticlepeer-review

Abstract

Inositol phosphates are widely produced throughout animal and plant tissues. Diphosphoinositol pentakisphosphate (InsP7) contains an energetic pyrophosphate bond. Here we demonstrate that disruption of inositol hexakisphosphate kinase 1 (InsP6K1), one of the three mammalian inositol hexakisphosphate kinases (InsP6Ks) that convert inositol hexakisphosphate (InsP6) to InsP7, conferred enhanced phosphatidylinositol-(3,4,5)-trisphosphate (PtdIns(3,4,5)P3)-mediated membrane translocation of the pleckstrin homology domain of the kinase Akt and thus augmented downstream PtdIns(3,4,5)P3 signaling in mouse neutrophils. Consequently, these neutrophils had greater phagocytic and bactericidal ability and amplified NADPH oxidase-mediated production of superoxide. These phenotypes were replicated in human primary neutrophils with pharmacologically inhibited InsP6Ks. In contrast, an increase in intracellular InsP7 blocked chemoattractant-elicited translocation of the pleckstrin homology domain to the membrane and substantially suppressed PtdIns(3,4,5)P3 -mediated cellular events in neutrophils. Our findings establish a role for InsP7 in signal transduction and provide a mechanism for modulating PtdIns(3,4,5)P3 signaling in neutrophils.

Original languageEnglish (US)
Pages (from-to)752-760
Number of pages9
JournalNature Immunology
Volume12
Issue number8
DOIs
StatePublished - Aug 2011

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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