Identification of a transporter complex responsible for the cytosolic entry of nitrogen-containing bisphosphonates

Zhou Yu, Lauren E. Surface, Chong Yon Park, Max A. Horlbeck, Gregory A. Wyant, Monther Abu-Remaileh, Timothy R. Peterson, David M. Sabatini, Jonathan S. Weissman, Erin K. O’shea

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10 Scopus citations

Abstract

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.

Original languageEnglish
Article numbere36620
JournaleLife
Volume7
DOIs
StatePublished - May 10 2018

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    Yu, Z., Surface, L. E., Park, C. Y., Horlbeck, M. A., Wyant, G. A., Abu-Remaileh, M., Peterson, T. R., Sabatini, D. M., Weissman, J. S., & O’shea, E. K. (2018). Identification of a transporter complex responsible for the cytosolic entry of nitrogen-containing bisphosphonates. eLife, 7, [e36620]. https://doi.org/10.7554/eLife.36620