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

First Author  Yu Z Year  2018
Journal  Elife Volume  7
PubMed ID  29745899 Mgi Jnum  J:334004
Mgi Id  MGI:7444877 Doi  10.7554/eLife.36620
Citation  Yu Z, et al. (2018) Identification of a transporter complex responsible for the cytosolic entry of nitrogen-containing bisphosphonates. Elife 7
abstractText  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.
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