eLife 7, e35588 (2018)

Phosphatidylinositol-4-phosphate (PtdIns4P) is involved in regulating vesicular traffic as well as nonvesicular lipid transport at the plasma membrane (PM), late endosomes/lysosomes, and the Golgi through binding to regulatory proteins. The phosphatase SAC1 regulates PtdIns4P levels and is localized primarily to the endoplasmic reticulum (ER). SAC1 has been proposed to regulate PtdIns4P levels at the PM, the Golgi and the endosomes through a ‘trans’ mechanism whereby SAC1 localizes to membrane-contact sites (MCSs) between the ER and these compartments. Evidence is also available for a ‘cis’ mechanism of SAC1 action on the PM- and Golgi-localized PtdIns4P that invokes separate lipid-transfer proteins. The transfer proteins move lipids from the ER to the PM or the Golgi and back-traffics a PtdIns4P molecule down its steep chemical gradient to the ER, where it can be degraded by SAC1. To distinguish between ‘cis’ and ‘trans’ SAC1 mechanisms, Zewe et al. first inhibited SAC1 and found that PtdIns4P accumulated at the ER. Furthermore, a fluorescently tagged SAC1 does not enrich at the ER-PM MCS. These results, a series of experiments using a chemically induced dimerization approach to induce ectopic ER–PM MCS, and measurements of PtdIns4P abundance together suggest a ‘cis’ mechanism for SAC1 and exclude a ‘trans’ mechanism, defining a critical role for SAC1 in driving countertransport of lipids against their chemical gradients.