A PtdIns4,5P2-regulated nuclear 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 (PtdIns4,5P2), the central component in the phosphoinositide signalling circuitry, is generated primarily by type I phosphatidylinositol 4-phosphate 5-kinases (PIPKIalpha, PIPKIbeta and PIPKIgamma). In addition to functions in the cytosol, phosphoinositides are present in the nucleus, where they modulate several functions; 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. Therefore, to determine roles for nuclear PtdIns4,5P2 we set out to identify proteins that interacted with the nuclear PIPK, PIPKIalpha. Here we show that PIPKIalpha 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 PIPKIalpha regulated-poly(A) polymerase) and that the activity of Star-PAP can be specifically regulated by PtdIns4,5P2. Star-PAP and PIPKIalpha 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.
Mellman
David L
DL
Program in Molecular and Cellular Pharmacology, University of Wisconsin Medical School, University of Wisconsin-Madison, 1300 University Avenue, Madison, Wisconsin 53706, USA.
Gonzales
Michael L
ML
Song
Chunhua
C
Barlow
Christy A
CA
Wang
Ping
P
Kendziorski
Christina
C
Anderson
Richard A
RA
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000235:genetics; D006801:Humans; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D009713:Nucleotidyltransferases; D018384:Oxidative Stress / Q000235:genetics; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011062:Polynucleotide Adenylyltransferase / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D026721:RNA 3' End Processing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D014158:Transcription, Genetic
D046912:Multiprotein Complexes; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D012333:RNA, Messenger; D051547:Heme Oxygenase-1; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; D009713:Nucleotidyltransferases; C586325:TUT1 protein, human; D011062:Polynucleotide Adenylyltransferase