A PtdIns4,5P2-regulatednuclear poly(A) polymerase controls expression of select mRNAs

Phosphoinositides are a family of lipid signalling molecules that regulate many cellular functions in eukaryotes. Phosphatidylinositol-4,5- bisphosphate ( PtdIns4,5P(2)), the central component in the phosphoinositide signalling circuitry, is generated primarily by type I phosphatidylinositol 4- phosphate 5- kinases ( PIPKI alpha, PIPKI beta and PIPKI gamma)(1). In addition to functions in the cytosol, phosphoinositides are present in the nucleus(2,3), where they modulate several functions(4-6); however, the mechanism by which they directly regulate nuclear functions remains unknown. PIPKIs regulate cellular functions through interactions with protein partners, often PtdIns4,5P(2) effectors, that target PIPKIs to discrete subcellular compartments, resulting in the spatial and temporal generation of PtdIns4,5P(2) required for the regulation of specific signalling pathways(1,7). Therefore, to determine roles for nuclear PtdIns4,5P(2) we set out to identify proteins that interacted with the nuclear PIPK, PIPKI alpha. Here we show that PIPKI alpha co- localizes at nuclear speckles and interacts with a newly identified non- canonical poly( A) polymerase, which we have termed Star- PAP ( nuclear speckle targeted PIPKIa regulated- poly( A) polymerase) and that the activity of Star- PAP can be specifically regulated by PtdIns4,5P(2). Star- PAP and PIPKIa function together in a complex to control the expression of select mRNAs, including the transcript encoding the key cytoprotective enzyme haem oxygenase- 1 ( refs 8, 9) and other oxidative stress response genes by regulating the 3 '-end formation of their mRNAs. Taken together, the data demonstrate a model by which phosphoinositide signalling works in tandem with complement pathways to regulate the activity of Star- PAP and the subsequent biosynthesis of its target mRNA. The results reveal a mechanism for the integration of nuclear phosphoinositide signals and a method for regulating gene expression.