Lipid transfer proteins initiate nuclear phosphoinositide signaling

The 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 PIPn synthesis. In contrast, nuclear PIPn signaling relies on poorly characterized non-membranous PIPn pools. Here we show that PITPs accumulate in the non-membranous nucleoplasm in response to stress and are necessary to generate nuclear PIPn pools. Class I PITPα/β bind p53 to form p53-PIPn complexes that activate nuclear Akt in response to stress, which inhibits apoptosis. These findings demonstrate an unexpected function for PITPα/β in nuclear PIPn signaling by generating membrane-free, protein-linked PIPn pools that are modified by PIP kinases/phosphatases to regulate protein function. In brief Phosphatidylinositol transfer proteins initiate the nuclear protein-associated PIPn network in membrane-free regions.