title: Inositol hexakisphosphate kinase 1 regulates neutrophil function in innate immunity by inhibiting phosphatidylinositol-(3,4,5)-trisphosphate signaling.
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.
authors.affiliation: Department of Pathology, Harvard Medical School, Department of Lab Medicine, Children's Hospital Boston, Boston, Massachusetts, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Prasad
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Jia
authors.forename: Anutosh
authors.initials: A
authors.lastname: Chakraborty
authors.forename: Yitang
authors.initials: Y
authors.lastname: Li
authors.forename: Supriya K
authors.initials: SK
authors.lastname: Jain
authors.forename: Jia
authors.initials: J
authors.lastname: Zhong
authors.forename: Saurabh Ghosh
authors.initials: SG
authors.lastname: Roy
authors.forename: Fabien
authors.initials: F
authors.lastname: Loison
authors.forename: Subhanjan
authors.initials: S
authors.lastname: Mondal
authors.forename: Jiro
authors.initials: J
authors.lastname: Sakai
authors.forename: Catlyn
authors.initials: C
authors.lastname: Blanchard
authors.forename: Solomon H
authors.initials: SH
authors.lastname: Snyder
authors.forename: Hongbo R
authors.initials: HR
authors.lastname: Luo
mesh_terms: D000818:Animals; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007295:Inositol Phosphates / Q000276:immunology*; D007527:Isoenzymes; D051379:Mice; D018345:Mice, Knockout; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology; D018129:Phosphatidylinositol Phosphates / Q000276:immunology*; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology; D012313:RNA / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D007295:Inositol Phosphates; D007527:Isoenzymes; D018129:Phosphatidylinositol Phosphates; C079849:1-diphosphoinositol pentakisphosphate; D009240:N-Formylmethionine Leucyl-Phenylalanine; D012313:RNA; D051057:Proto-Oncogene Proteins c-akt; D017856:Phosphotransferases (Phosphate Group Acceptor); C099438:inositol hexakisphosphate kinase; D004121:Dimethyl Sulfoxide