Lipid Transfer Proteins and PI4KIIα Initiate Nuclear p53-Phosphoinositide Signaling

Abstract

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 the 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 PI3,4,5P ₃ -dependent mechanism in non-membranous regions of the nucleus. This pathway is dependent on a source of nuclear PIP _n s 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 signaling in the nucleus. Additionally, the PI 4-kinase PI4KIIα binds to p53 and the PITPs to catalyze 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 way, 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 novel therapeutic targets in this pathway for diseases like cancer.

Significance statement: PI transfer proteins and a PI 4-kinase initiate nuclear p53-phosphoinositide signaling in membrane-free regions to promote stress resistance.