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

By 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 O'Shea

Posted 27 Mar 2018
bioRxiv DOI: 10.1101/289835

Nitrogen-containing-bisphosphonates (N-BPs) are 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. 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.

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