Type I phosphatidylinositol-4, 5-bisphosphate 4-phosphatase regulates stress-induced apoptosis

A recently discovered phosphaticlylinositol monophosphate, phosphaticlylinositol 5-phosphate (Ptdlns-5-13), plays an important role in nuclear signaling by influencing p53-dependent apoptosis. It interacts with a plant homeodomain finger of inhibitor of growth protein-2, causing an increase in the acetylation and stability of p53. Here we show that type I phosphatidylinositol-4,5-bisphosphate 4-phosphatase (type I 4-phosphatase), an enzyme that dephosphorylates phosphaticlylinositol 4,5-bisphosphate (Ptdlns-45-PA, forming Ptdlns-5-P in vitro, can increase the cellular levels of Ptdlns-5-P. When HeLa cells were treated with the I DNA-damaging agents etoposide or doxorubicin, type I 4-phosphatase translocated to the nucleus and nuclear levels of PtdIns-5-P increased. This action resulted in increased p53 acetylation, which stabilized p53, leading to increased apoptosis. Overexpression of type I 4-phosphatase increased apoptosis, whereas RNAi of the enzyme diminished it. The half-life of p53 was shortened from 7 h to 1.8 h upon RNAi of type I 4-phosphatase. This enzyme therefore controls nuclear levels of Ptdlns-5-P and thereby p53-dependent apoptosis.