Inositol Hexakisphosphate Kinase 1 Regulates Neutrophil Function in Innate Immunity by Inhibiting Phosphatidylinositol-(3,4,5)-trisphosphate Signaling

Overview

Journal Nat Immunol

Date 2011 Jun 21

PMID 21685907

Citations 54

Authors

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

Affiliations

Soon will be listed here.

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.

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