Predominant localization of phosphatidylserine at the cytoplasmic leaflet of the ER, and its TMEM16K-dependent redistribution

Significance Phospholipids in the plasma membrane are scrambled between the two leaflets by TMEM16 proteins. Some TMEM16 family members are also present in intracellular membranes, but whether they scramble phospholipids inside cells has not been demonstrated. To address this question, we developed a method to study the distribution of phosphatidylserine (PtdSer) in individual membrane leaflets. Using this method, we found that PtdSer is present in the cytoplasmic leaflet of the endoplasmic reticulum and in the nuclear membrane, and that an increase in intracellular Ca 2+ causes the PtdSer in intracellular membranes to be redistributed in a TMEM16K-dependent manner. These results indicate that phospholipids in the endoplasmic reticulum are redistributed by a mechanism similar to that in the plasma membrane.