Nir2 Plays a Central Role in ER-PM Junctions Maintaining Phosphoinositide Signaling Competence

During phospholipase C activation, large amounts of phosphoinositide lipids are consumed while generating the second messengers, diacylglycerol (DG) and InsP3. The small PtdIns(4,5)P2 pool is turned over multiple times and it has been evident that the plasma membrane (PM) inositide pools need to be replenished for sustained signaling with newly synthesized phosphatidylinositol (PtdIns) originating from the ER. Conversely, phosphatidic acid (PtdOH) generated via DG in the PM has to return to the ER where it is utilized for PtdIns synthesis. Although PtdIns transfer protein has been postulated to transport PtdIns from the ER to the PM, the protein responsible for PtdOH transport in the other direction has remained elusive. In this study we used a combination of methods all based on intact cells and found that depletion of Nir2, a homolog of the Drosophila RdgB protein, which has previously been identified as a PtdIns transfer protein, causes a defect both in the utilization of PtdOH at the PM and the synthe...