Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States; Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
Lauren E Surface
Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States; Faculty of Arts and Sciences Center for Systems Biology, Harvard University, Cambridge, United States; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States; Howard Hughes Medical Institute, Bethesda, United States
Chong Yon Park
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
Howard Hughes Medical Institute, Bethesda, United States; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States; Center for RNA Systems Biology, University of California, San Francisco, San Francisco, United States
Gregory A Wyant
Howard Hughes Medical Institute, Bethesda, United States; Whitehead Institute for Biomedical Research, Cambridge, United States; Department of Biology, Massachusetts Institute of Technology, Cambridge, United States; Koch Institute for Integrative Cancer Research, Cambridge, United States; Broad Institute of MIT and Harvard, Cambridge, United States
Monther Abu-Remaileh
Howard Hughes Medical Institute, Bethesda, United States; Whitehead Institute for Biomedical Research, Cambridge, United States; Department of Biology, Massachusetts Institute of Technology, Cambridge, United States; Koch Institute for Integrative Cancer Research, Cambridge, United States; Broad Institute of MIT and Harvard, Cambridge, United States
Timothy R Peterson
Division of Bone & Mineral Diseases, Department of Genetics, Institute for Public Health, Washington University School of Medicine, St. Louis, United States
David M Sabatini
Howard Hughes Medical Institute, Bethesda, United States; Whitehead Institute for Biomedical Research, Cambridge, United States; Department of Biology, Massachusetts Institute of Technology, Cambridge, United States; Koch Institute for Integrative Cancer Research, Cambridge, United States; Broad Institute of MIT and Harvard, Cambridge, United States
Howard Hughes Medical Institute, Bethesda, United States; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States; Center for RNA Systems Biology, University of California, San Francisco, San Francisco, United States
Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States; Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States; Faculty of Arts and Sciences Center for Systems Biology, Harvard University, Cambridge, United States; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States; Howard Hughes Medical Institute, Bethesda, United States
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.
