Lipid transfer proteins and PI4KIIα initiate nuclear p53-phosphoinositide signaling

Phosphoinositide (PIP_n) 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-PIP_n complexes (p53-PIP_n 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 PIP_ns that is poorly characterized. Here we report that a subset of PI transfer proteins (PITPs), which transport PI between membranes to enable membrane-localized PIP_n synthesis, also interact with p53 in the nucleus upon genotoxic stress. Class I PITPs (PITPα/β) specifically supply the PI required for the generation of p53-PIP_n complexes and subsequent p53 signaling in the nucleus. The PI 4-kinase PI4KIIα 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-PIP_n complexes that regulate p53 stability, nuclear Akt activation and genotoxic stress resistance. In this pathway, PITPα/β and PI4KIIα bind p53 and collaborate to initiate p53-PIP_n signaling by mechanisms that require PI transfer by PITPα/β and the catalytic activity of PI4KIIα. Moreover, the identification of these critical upstream regulators of p53-PIP_n signaling point to PITPα/β and PI4KIIα as potential therapeutic targets in this pathway for mutant p53 driven cancers.