Lipid transfer proteins initiate nuclear phosphoinositide signaling

Phosphoinositide (PIPn) messengers are present in non-membranous regions of nuclei where they are assembled into a phosphatidylinositol (PI) 3-kinase (PI3K)/Akt pathway that is distinct from the cytosolic membrane-localized pathway. In the nuclear pathway, PI kinases/phosphatases bind the p53 tumor suppressor protein (wild-type and mutant) to generate p53-PIPn complexes (p53-PIPn signalosome) that activate Akt by a PI3,4,5P3-dependent mechanism in non-membranous regions of the nucleus. This pathway is dependent on a source of nuclear PIPns that is poorly characterized. Here we report that a subset of PI transfer proteins (PITPs), which transport PI between membranes to enable membrane-localized PIPn synthesis, also interact with p53 in the nucleus upon genotoxic stress. Class I PITPs (PITP/{beta}) specifically supply the PI required for the generation of p53-PIPn complexes and subsequent signaling in the nucleus. Additionally, the PI 4-kinase PI4KII binds to p53 and the PITPs to catalyze the formation of p53-PI4P. p53-PI4P is then sequentially phosphorylated to synthesize p53-PIPn complexes that regulate p53 stability, nuclear Akt activation and genotoxic stress resistance. In this way, PITP/{beta} and PI4KII bind p53 and collaborate to initiate p53-PIPn signaling by mechanisms that require PI transfer by PITP/{beta} and the catalytic activity of PI4KII. Moreover, the identification of these critical upstream regulators of p53-PIPn signaling point to PITP/{beta} and PI4KII as potential therapeutic targets in this pathway for diseases like cancer. In BreifPhosphatidylinositol transfer proteins and a PI 4-kinase initiate nuclear p53-PIPn signaling in membrane-free regions.