1. Program in Molecular and Cellular Pharmacology,
2. Department of Pharmacology, and,
3. Department of Biostatistics and Medical Informatics, University of Wisconsin Medical School, University of Wisconsin-Madison, 1300 University Avenue, Madison, Wisconsin 53706, USA
4. These authors contributed equally to this work.

Correspondence to: Richard A. Anderson^1,2 Correspondence and requests for materials should be addressed to R.A.A. (Email: raanders@wisc.edu).

Phosphoinositides are a family of lipid signalling molecules that regulate many cellular functions in eukaryotes. Phosphatidylinositol-4,5-bisphosphate (PtdIns4,5P₂), the central component in the phosphoinositide signalling circuitry, is generated primarily by type I phosphatidylinositol 4-phosphate 5-kinases (PIPKI, PIPKI and PIPKI)¹. In addition to functions in the cytosol, phosphoinositides are present in the nucleus^{2, 3}, where they modulate several functions^{4, 5, 6}; however, the mechanism by which they directly regulate nuclear functions remains unknown. PIPKIs regulate cellular functions through interactions with protein partners, often PtdIns4,5P₂ effectors, that target PIPKIs to discrete subcellular compartments, resulting in the spatial and temporal generation of PtdIns4,5P₂ required for the regulation of specific signalling pathways^{1, 7}. Therefore, to determine roles for nuclear PtdIns4,5P₂ we set out to identify proteins that interacted with the nuclear PIPK, PIPKI. Here we show that PIPKI 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 PIPKI regulated-poly(A) polymerase) and that the activity of Star-PAP can be specifically regulated by PtdIns4,5P₂. Star-PAP and PIPKI 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.

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