Abstract 2476 Regulation of PI(4,5)P2 homeostasis at ER-plasma membrane contact sites by Nir proteins

This is the authors' abstract. We don't add key points for this paper.

Endoplasmic reticulum (ER)-plasma membrane contact sites are subcellular structures where the ER is tethered to the plasma membrane to facilitate exchange of lipids and calcium signals between the two membrane compartments. The phospholipid, phosphatidylinositol (PI) 4,5-bisphosphate (PI[4,5]P2), controls many cellular functions in the plasma membrane. Following stimulation of many cell surface receptors, PI(4,5)P2 is hydrolyzed to generate second messengers for downstream signaling. It is crucial to quickly replenish PI(4,5)P2 in the plasma membrane following receptor-induced hydrolysis to sustain cell signaling and to maintain PI(4,5)P2-dependent plasma membrane functions. We have previously shown that lipid transfer proteins Nir2 and Nir3 dynamically translocate into ER-plasma membrane contact sites to mediate exchange of phosphatidylinositol and phosphatidic acids between the ER and the plasma membrane for PI(4,5)P2 replenishment in receptor-stimulated cells. Knockdown of Nir2 and Nir3 suppressed the replenishment of plasma membrane PI(4,5)P2 and calcium signaling in receptor-stimulated cells. A third mammalian Nir protein, Nir1, has been linked to several human diseases including retinal dystrophy. Unlike Nir2 and Nir3, Nir1 lacks a lipid transfer protein domain and pre-localizes at ER-plasma membrane contact sites in resting cells. We found that Nir1 expression promotes Nir2 localization at ER-plasma membrane contact sites to mediate PI(4,5)P2 replenishment following receptor stimulation. We further characterized the mechanism by which Nir1 binds Nir2. We propose that Nir1 and Nir2 form heterodimers to regulate plasma membrane PI(4,5)P2 homeostasis at ER-plasma membrane contact sites during receptor-induced calcium signaling. This work is supported by National Institute of Health R01 grant GM144479.