Identification of a transporter complex responsible for the cytosolic entry of nitrogen-containing bisphosphonates
Author(s)
Wyant, Gregory A; Abu-Remaileh, Monther; Sabatini, David M.
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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.
Date issued
2018-05-10Department
Whitehead Institute for Biomedical Research; Massachusetts Institute of Technology. Department of Biology; Koch Institute for Integrative Cancer Research at MITJournal
eLife
Publisher
eLife Sciences Publications, Ltd
Citation
Yu, Zhou , et al. “Identification of a transporter complex responsible for the cytosolic entry of nitrogen-containing bisphosphonates.” eLife 7 (2018): e36620 © 2018 The Author(s)
Version: Final published version
ISSN
2050-084X
Keywords
General Biochemistry, Genetics and Molecular Biology, General Immunology and Microbiology, General Neuroscience, General Medicine