Phosphatidylinositol 4,5-bisphosphate Homeostasis Regulated by Nir2 and Nir3 at Endoplasmic Reticulum-Plasma Membrane Junctions [Lipids]

April 17th, 2015 by Chang, C.-L., Liou, J.

Phosphatidylinositol (PI) 4,5-bisphosphate (PIP2) at the plasma membrane (PM) constitutively controls many cellular functions, and its hydrolysis via receptor stimulation governs cell signaling. The PI transfer protein (PITP) Nir2 is essential for replenishing PM PIP2 following receptor-induced hydrolysis, but key mechanistic aspects of this process remain elusive. Here we demonstrate that PI at the membrane of the endoplasmic reticulum (ER) is required for the rapid replenishment of PM PIP2 mediated by Nir2. Nir2 detects PIP2 hydrolysis and translocates to ER-PM junctions via binding to phosphatidic acid (PA). With distinct PA binding abilities and PITP activities, Nir2 and its homolog Nir3 differentially regulate PIP2 homeostasis in cells during intense receptor stimulation and in the resting state, respectively. Our study reveals that Nir2 and Nir3 work in tandem to achieve different levels of feedback based on the consumption of PM PIP2, and function at ER-PM junctions to mediate non-vesicular lipid transport between the ER and the PM.