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

被引：69

作者：

Prasad, Amit ^{[1
]}

Jia, Yonghui ^{[1
]}

Chakraborty, Anutosh ^{[2
,3
]}

Li, Yitang ^{[1
]}

Jain, Supriya K. ^{[1
]}

Zhong, Jia ^{[1
]}

Roy, Saurabh Ghosh ^{[1
]}

Loison, Fabien ^{[1
]}

Mondal, Subhanjan ^{[1
]}

Sakai, Jiro ^{[1
]}

Blanchard, Catlyn ^{[1
]}

Snyder, Solomon H. ^{[2
,3
]}

Luo, Hongbo R. ^{[1
,4
]}

机构：

[1] Harvard Univ, Sch Med, Dept Pathol, Dept Lab Med,Childrens Hosp Boston, Boston, MA 02115 USA

[2] Johns Hopkins Univ, Sch Med, Dept Neurosci, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA

[4] Harvard Univ, Sch Med, Dana Farber Harvard Canc Ctr, Boston, MA USA

来源：

NATURE IMMUNOLOGY | 2011年 / 12卷 / 08期

基金：

美国国家卫生研究院;

关键词：

CHRONIC GRANULOMATOUS-DISEASE; PLECKSTRIN HOMOLOGY DOMAIN; OVARIAN-CARCINOMA CELLS; TUMOR-SUPPRESSOR PTEN; HYDROGEN-PEROXIDE; NADPH-OXIDASE; DIPHOSPHOINOSITOL POLYPHOSPHATES; PYROPHOSPHATES; CHEMOTAXIS; P47(PHOX);

D O I：

10.1038/ni.2052

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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)P(3))-mediated membrane translocation of the pleckstrin homology domain of the kinase Akt and thus augmented downstream PtdIns(3,4,5)P(3) 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)P(3)-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)P(3) signaling in neutrophils.

引用

页码：752 / U144

页数：10

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