Lipid transfer proteins initiate nuclear phosphoinositide signaling

SummaryThe membrane-localized phosphatidylinositol (PI) 3-kinase (PI3K)/Akt pathway regulates cell growth and is aberrantly activated in cancer. Recent studies reveal a distinct nuclear PI3K/Akt pathway involving PI phosphate (PIP) kinases that bind the tumor suppressor protein p53 (wild-type and mutant) to generate nuclear p53-polyphosphoinositide (PIPn) complexes that activate Akt. In the membrane pathway, PI transfer proteins (PITPs) transport PI, the precursor of PIPns, to endomembranes to enable PIPnsynthesis. In contrast, nuclear PIPnsignaling relies on poorly characterized non-membranous PIPnpools. Here we show that PITPs accumulate in the non-membranous nucleoplasm in response to stress and are necessary to generate nuclear PIPnpools. Class I PITPα/β bind p53 to form p53-PIPncomplexes that activate nuclear Akt in response to stress, which inhibits apoptosis. These findings demonstrate an unexpected function for PITPα/β in nuclear PIPnsignaling by generating membrane-free, protein-linked PIPnpools that are modified by PIP kinases/phosphatases to regulate protein function.In briefPhosphatidylinositol transfer proteins initiate the nuclear protein-associated PIPnnetwork in membrane-free regions.