Identification of a transporter complex responsible for the cytosolic entry of nitrogen-containing bisphosphonates
Name
elife-36620-v2.pdf
Description
Published version
Size
4 MB
Format
Adobe PDF
Checksum (MD5)
da9864d953d6275663ad7f5c15dc08c6
Author(s)
Wyant, Gregory A
Abu-Remaileh, Monther
Sabatini, David M.
Date Issued
May 10, 2018
Journal
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
Abstract
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.
Subjects
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology
General Neuroscience
General Medicine
MIT Department
Whitehead Institute for Biomedical Research
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution 4.0 International license
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.7554/elife.36620
