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Phosphoinositides (PIs) regulate mast cell (MC) secretory granule (SG) biogenesis and exocytosis, yet their compartment-specific roles in receptor signaling and secretion remain unclear. Using a rapamycin-inducible dimerization system to recruit site-specific lipid phosphatases to either the plasma membrane or the SGs, we assessed the impact of spatially restricted PI depletion on secretion triggered by FcεRI activation, the MRGPRX2 ligand substance P (SP), or receptor-independent calcium/phorbol ester stimulation. Our data reveal distinct and shared PI requirements for coupling FcεRI and MRGPRX2 signaling to the exocytic machinery and uncover PI derivatives that act locally at the SGs to modulate granule release. Together, these findings show that individual PIs differentially orchestrate allergic and neurogenic secretion pathways and fine-tune SG exocytosis through site-specific functions.
Omari-Manaa et al. (Sat,) studied this question.