Department of Pathology, Harvard Medical School, Department of Lab Medicine, Children's Hospital Boston, Boston, Massachusetts, USA.
Nat Immunol. 2011 Jun 19;12(8):752-60. doi: 10.1038/ni.2052.
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.
肌醇磷酸盐广泛存在于动植物组织中。双磷酸肌醇 pentakisphosphate (InsP7) 含有一个高能焦磷酸键。在这里，我们证明了肌醇六磷酸激酶 1 (InsP6K1) 的破坏，InsP6K1 是三种将肌醇六磷酸 (InsP6) 转化为 InsP7 的哺乳动物肌醇六磷酸激酶之一，导致激酶 Akt 的 pleckstrin 同源结构域与磷脂酰肌醇-(3,4,5)-三磷酸 (PtdIns(3,4,5)P3) 介导的膜易位增加，从而增强下游 PtdIns(3,4,5)P3 信号。因此，这些中性粒细胞具有更强的吞噬和杀菌能力，并增强了 NADPH 氧化酶介导的超氧产生。这些表型在人原代中性粒细胞中通过药理学抑制 InsP6Ks 得到复制。相比之下，细胞内 InsP7 的增加阻止了趋化因子诱导的 pleckstrin 同源结构域向膜的易位，并大大抑制了中性粒细胞中 PtdIns(3,4,5)P3 介导的细胞事件。我们的发现确立了 InsP7 在信号转导中的作用，并为调节中性粒细胞中 PtdIns(3,4,5)P3 信号提供了一种机制。
