Abstract
Inositol phosphates (InsP) are widely produced throughout animal and plant tissues. Diphosphoinositol pentakisphosphate (InsP7) contains an energetic pyrophosphate bond. Here, we demonstrate that disruption of InsP6K1, one of the three mammalian InsP6Ks that convert InsP6 to InsP7, confers enhanced PtdIns(3,4,5)P3-mediated membrane translocation of Akt pleckstrin homology (PH) domain and thus augments downstream PtdIns(3,4,5)P3 signaling in murine neutrophils. Consequently, these neutrophils exhibited elevated phagocytic and bactericidal capabilities and amplified NADPH oxidase-mediated superoxide production. These phenotypes were replicated in human primary neutrophils with pharmacologically inhibited InsP6Ks. By contrast, increasing intracellular InsP7 amounts blocked chemoattractant-elicited PH domain membrane translocation and dramatically suppressed PtdIns(3,4,5)P3-mediated cellular events in neutrophils. These 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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