Regulation of anaphylactic responses by phosphatidylinositol phosphate kinase type I α

The membrane phospholipid phosphatidylinositol 4, 5-bisphosphate [PI(4,5)P(2)] is a critical signal transducer in eukaryotic cells. However, the physiological roles of the type I phosphatidylinositol phosphate kinases (PIPKIs) that synthesize PI(4,5)P(2) are largely unknown. Here, we show that the α isozyme of PIPKI (PIPKIα) negatively regulates mast cell functions and anaphylactic responses. In vitro, PIPKIα-deficient mast cells exhibited increased degranulation and cytokine production after Fcɛ receptor-I cross-linking. In vivo, PIPKIα(−/−) mice displayed enhanced passive cutaneous and systemic anaphylaxis. Filamentous actin was diminished in PIPKIα(−/−) mast cells, and enhanced degranulation observed in the absence of PIPKIα was also seen in wild-type mast cells treated with latrunculin, a pharmacological inhibitor of actin polymerization. Moreover, the association of FcɛRI with lipid rafts and FcɛRI-mediated activation of signaling proteins was augmented in PIPKIα(−/−) mast cells. Thus, PIPKIα is a negative regulator of FcɛRI-mediated cellular responses and anaphylaxis, which functions by controlling the actin cytoskeleton and dynamics of FcɛRI signaling. Our results indicate that the different PIPKI isoforms might be functionally specialized.