TY - JOUR TI - Identification of a transporter complex responsible for the cytosolic entry of nitrogen-containing bisphosphonates AU - Yu, Zhou AU - Surface, Lauren E AU - Park, Chong Yon AU - Horlbeck, Max A AU - Wyant, Gregory A AU - Abu-Remaileh, Monther AU - Peterson, Timothy R AU - Sabatini, David M AU - Weissman, Jonathan S AU - O'Shea, Erin K A2 - Cole, Philip A VL - 7 PY - 2018 DA - 2018/05/10 SP - e36620 C1 - eLife 2018;7:e36620 DO - 10.7554/eLife.36620 UR - https://doi.org/10.7554/eLife.36620 AB - Nitrogen-containing-bisphosphonates (N-BPs) are a class of drugs widely prescribed to treat osteoporosis and other bone-related diseases. Although previous studies have established that N-BPs function by inhibiting the mevalonate pathway in osteoclasts, the mechanism by which N-BPs enter the cytosol from the extracellular space to reach their molecular target is not understood. Here, we implemented a CRISPRi-mediated genome-wide screen and identified SLC37A3 (solute carrier family 37 member A3) as a gene required for the action of N-BPs in mammalian cells. We observed that SLC37A3 forms a complex with ATRAID (all-trans retinoic acid-induced differentiation factor), a previously identified genetic target of N-BPs. SLC37A3 and ATRAID localize to lysosomes and are required for releasing N-BP molecules that have trafficked to lysosomes through fluid-phase endocytosis into the cytosol. Our results elucidate the route by which N-BPs are delivered to their molecular target, addressing a key aspect of the mechanism of action of N-BPs that may have significant clinical relevance. KW - mechanism of action KW - membrane transporter KW - lysosomes KW - genome-wide screening JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -