Agonist- and stress-driven compartmentalized phosphoinositide signaling in cells

Phosphoinositides (PIPs) are essential lipid messengers that regulate cellular responses to external stimuli and stress through spatially organized signaling pathways. In recent years, compartment-specific mechanisms by which PIP signaling integrates diverse cellular processes have been extensively expanded. This review discusses the distinct roles of PIP signaling across cellular compartments, including the plasma membrane, endosomes, lysosomes, protein scaffolds, and the nucleus. PIPs coordinate key processes such as receptor trafficking, cytoskeletal remodeling, autophagy, and signal transduction. Dynamic lysosomal PIP switches regulate critical functions like nutrient sensing, mTORC1 activity, and membrane repair, emphasizing their adaptability in maintaining cellular homeostasis. Furthermore, emerging evidence highlights nuclear PIP signaling in transcriptional regulation, DNA repair, and oncogenic pathways. Dysregulation of PIP signaling pathways is implicated in diseases such as cancer, neurodegeneration, and lysosomal storage disorders, underscoring their therapeutic potential in various pathological conditions.