Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 67,258 bioRxiv papers from 296,039 authors.
Identification and characterization of a transporter complex responsible for the cytosolic entry of nitrogen-containing bisphosphonates
Lauren E Surface,
Chong Yon Park,
Max A Horlbeck,
Gregory A Wyant,
Timothy R Peterson,
David M Sabatini,
Jonathan S. Weissman,
Posted 27 Mar 2018
bioRxiv DOI: 10.1101/289835
Posted 27 Mar 2018
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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