Inositol 1,3,4,5-tetrakisphosphate negatively regulates phosphatidylinositol-3,4,5-trisphosphate signaling in neutrophils

Many neutrophil functions are regulated by phosphatidylinositol-3,4,5-trisphosphate (Ptdlns(3,4,5)P3) that mediates protein membrane translocation via binding to pleckstrin homolog (PH) domains within target proteins. Here we show that inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4), a cytosolic small molecule, bound the same PH domain of target proteins and competed for binding to Ptdlns(3,4,5)P3. In neutrophils, chemoattractant stimulation triggered rapid elevation in lns(1,3,4,5)P4 concentration. Depletion of lns(1,3,4,5)P4 by deleting the gene encoding lnsP3KB, which converts Ins(1,4,5)P3 to Ins(1,3,4,5)P4, enhanced membrane translocation of the Ptdins(3,4,5)P3specific PH domain. This led to enhanced sensitivity to chemoattractant stimulation, elevated superoxide production, and enhanced neutrophil recruitment to inflamed peritoneal cavity. On the contrary, augmentation of intracellular Ins(1,3,4,5)P4 concentration blocked PH domainmediated membrane translocation of target proteins and dramatically decreased the sensitivity of neutrophils to chemoattractant stimulation. These findings establish a role for lns(1,3,4,5)P4 in cellular signal transduction pathways and provide another mechanism for modulating Ptdlns(3,4,5)P3 signaling in neutrophils.