The Signaling Phospholipid Pip3 Functions As A Ligand Hormone For Nuclear Receptors

The existence of nuclear, non-membrane pools of signaling phosphoinositides (PIPs) was reported over two decades ago. Consistent with these early reports, lipid-modifying enzymes responsible for phosphoinositide metabolism are found in the nucleus. How the lipid tails of nuclear phosphoinositides can exist in a non-membrane environment is a major unresolved question. Our prior work showed that bacterial phospholipids bind to NR5A nuclear receptors (Krylova et al, Cell 2005); these transcription factors are important in regulating steroid and cholesterol homeostasis. Here, we report that the phosphoinositides PIP2 and PIP3 bind both hLRH-1 (NR5A2) and hSF-1 (NR5A1) with nM affinity. New X-ray crystal structures of SF-1 (2.4 A) and LRH-1 (1.8 A) bound to PIP3 reveal the lipid tails of PIP3 nestled into the hydrophobic cavity with the headgroup solvent exposed and poised for modification by lipid kinases and phosphatases, as we previously reported (Blind et al, Sci Signaling 2012). As NR5A ligands, PIPs dive...