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Elife. 2018 May 10;7. pii: e36620. doi: 10.7554/eLife.36620.

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

Yu Z1,2, Surface LE1,3,4,5, Park CY6, Horlbeck MA5,6,7, Wyant GA5,8,9,10,11, Abu-Remaileh M5,8,9,10,11, Peterson TR12, Sabatini DM5,8,9,10,11, Weissman JS5,6,7, O'Shea EK1,2,3,4,5.

Author information

1
Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States.
2
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States.
3
Faculty of Arts and Sciences Center for Systems Biology, Harvard University, Cambridge, United States.
4
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States.
5
Howard Hughes Medical Institute, Bethesda, United States.
6
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.
7
Center for RNA Systems Biology, University of California, San Francisco, San Francisco, United States.
8
Whitehead Institute for Biomedical Research, Cambridge, United States.
9
Department of Biology, Massachusetts Institute of Technology, Cambridge, United States.
10
Koch Institute for Integrative Cancer Research, Cambridge, United States.
11
Broad Institute of MIT and Harvard, Cambridge, United States.
12
Division of Bone & Mineral Diseases, Department of Genetics, Institute for Public Health, Washington University School of Medicine, St. Louis, United States.

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.

KEYWORDS:

biochemistry; cell biology; chemical biology; genome-wide screening; human; lysosomes; mechanism of action; membrane transporter; mouse

Comment in

PMID:
29745899
PMCID:
PMC6021172
DOI:
10.7554/eLife.36620
[Indexed for MEDLINE]
Free PMC Article

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