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

O'Shea, E. K.; 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.

doi:10.1101/289835

bioRxiv · 10.1101/289835

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

O'Shea, E. K.·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.

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Abstract

AbstractNitrogen-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. 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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O'Shea, E. K., 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.. 2018-03-27. Identification and characterization of a transporter complex responsible for the cytosolic entry of nitrogen-containing bisphosphonates. https://doi.org/10.1101/289835

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