Lipid Transfer Proteins and PI4KIIα Initiate Nuclear p53-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 one 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 PI3,4,5P3dependent 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/) specifically supply the PI required for the generation of p53-PIPn complexes and subsequent p53 signaling in the nucleus.The PI 4-kinase PI4KII binds to p53 and together with the PITPs are necessary for 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 pathway, PITP/ and PI4KII bind p53 and collaborate to initiate p53-PIPn signaling by mechanisms that require PI transfer by PITP/ and the catalytic activity of PI4KII.Moreover, the identification of these critical upstream regulators of p53-PIPn signaling point to PITP/ and PI4KII as potential therapeutic targets in this pathway for mutant p53 driven cancers.