Lipid transfer proteins and a PI 4-kinase initiate nuclear phosphoinositide signaling.

Unlabelled: Phosphoinositide (PIP ) 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 complexes that regulate Akt activation. However, this pathway is dependent on poorly characterized nuclear PIP pools. Here we report that PI transfer proteins (PITPs), which transport PI between membranes to enable membrane-localized PIP synthesis, accumulate in the nucleoplasm in response to stress and supply nuclear PIP 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 complexes that regulate nuclear Akt activation and stress-resistance. Remarkably, PITPα/β and PI4KIIα initiate PIP -linkage to multiple proteins that are detectable by immunoblotting and [ H] -inositol metabolic labeling and are resistant to denaturation, suggesting a posttranslational modification.

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