Inositol 1,3,4,5-tetrakisphosphate negatively regulates chemoattractant-elicited PtdIns(3,4,5)P3 signaling in neutrophils

• Published in: Immunity (Cambridge, Mass.) Mass.), 2007-09, Vol.27 (3), p.453-467
• Main Authors: Jia, Yonghui, Subramanian, Kulandayan K., Erneux, Christophe, Pouillon, Valerie, Hattori, Hidenori, Jo, Hakryul, You, Jian, Zhu, Daocheng, Schurmans, Stephane, Luo, Hongbo R.
• Format: Article
• Language: English
• ISSN: 1074-7613
• DOI: 10.1016/j.immuni.2007.07.016

Many neutrophil functions are mediated by PtdIns(3,4,5)P3, an essential cellular signaling molecule that exerts its function by mediating protein translocation via binding to their pleckstrin homolog (PH)-domains. In mammalian cells, its activity was previously thought to be dependent solely upon concentrations of PtdIns(3,4,5)P3 in the plasma membrane. Here we show that inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4), a cytosolic small molecule, binds the same PH domain and compete for its binding to PtdIns(3,4,5)P3. In neutrophils, chemoattractant stimulation triggers rapid elevation in Ins(1,3,4,5)P4 level. Depletion of Ins(1,3,4,5)P4 by deleting InsP3KB, which converts Ins(1,4,5)P3 to Ins(1,3,4,5)P4, enhances the membrane translocation of PtdIns(3,4,5)P3 specific PH domain, thus augments the PtdIns(3,4,5)P3 downstream signals, leading 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 level blocks chemoattractant-elicited PH domain membrane translocation and dramatically decreases the sensitivity of neutrophils to chemoattractant stimulation. These findings establish a novel role for Ins(1,3,4,5)P4 in cellular signal transduction pathways and provide an alternative mechanism for modulating PtdIns(3,4,5)P3 signaling in neutrophils, namely relative levels of Ins(1,3,4,5)P4 and PtdIns(3,4,5)P3.