Nuclear phosphoinositides: An exploration into their regulation, roles and physico-chemical environment

Polyphosphoinositides are phospholipids consisting of a diacylglycerol backbone linked to an inositol headgroup that can be phosphorylated at three positions, generating seven distinct lipid species. Their levels are tightly regulated by coordinated kinase, phosphatase, and phospholipase activities, each responsive to diverse cellular cues. The functional diversity of phosphoinositides arises from their ability to bind specific protein domains, thereby influencing protein localisation, activity, and interaction networks. Although traditionally associated with membrane-bound compartments, phosphoinositides are also present within the nucleus, not only at the nuclear envelope but also within a variety of membrane-less nuclear structures. The identification of nuclear phosphoinositide-binding proteins has revealed that phosphoinositides contribute to the regulation of multiple nuclear processes, including transcription, RNA maturation and export, DNA damage responses, and broader nuclear stress signalling. In this review, we summarise the mechanisms by which nuclear phosphoinositides are generated, spatially organised, and interpreted by downstream effectors, and we highlight key outstanding questions that remain to be resolved.