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.
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for the two CRISPRi screens shown in Figure 1 and its figure supplement.
Data from: Identification and characterization of a transporter complex responsible for the cytosolic entry of nitrogen-containing-bisphosphonatesAvailable at Dryad Digital Repository under a CC0 Public Domain Dedication.
- Zhou Yu
- Lauren E Surface
- Chong Yon Park
- Max A Horlbeck
- Gregory A Wyant
- Monther Abu-Remaileh
- David M Sabatini
- Jonathan S Weissman
- Erin K O'Shea
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Philip A Cole, Harvard Medical School, United States
© 2018, Yu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.