Lipid transfer proteins and a PI 4-kinase initiate nuclear 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 the nuclear pathway, PI kinases/phosphatases bind the p53 tumor suppressor protein (wild-type and mutant) to generate p53-PIP _n complexes that regulate Akt activation. However, this pathway is dependent on poorly characterized nuclear PIP _n pools. Here we report that PI transfer proteins (PITPs), which transport PI between membranes to enable membrane-localized PIP _n synthesis, accumulate in the nucleoplasm in response to stress and supply nuclear PIP _n pools. PITPα/β and the PI 4-kinase PI4KIIα bind p53 and are required to generate p53-PI4P, which is further phosphorylated to synthesize p53-PIP _n complexes that regulate nuclear Akt activation and stress-resistance. Remarkably, PITPα/β and PI4KIIα initiate PIP _n -linkage to multiple proteins that are detectable by immunoblotting and [ ³ H] myo -inositol metabolic labeling and are resistant to denaturation, suggesting a posttranslational modification.

In brief: Phosphatidylinositol transfer proteins initiate the nuclear PIP _n -linked protein network in membrane-free regions.