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

  1. Zhou Yu
  2. Lauren E Surface
  3. Chong Yon Park
  4. Max A Horlbeck
  5. Gregory A Wyant
  6. Monther Abu-Remaileh
  7. Timothy R Peterson
  8. David M Sabatini
  9. Jonathan S Weissman
  10. Erin K O'Shea  Is a corresponding author
  1. Harvard University, United States
  2. University of California, San Francisco, United States
  3. Whitehead Institute for Biomedical Research, United States
  4. Washington University School of Medicine, 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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for the two CRISPRi screens shown in Figure 1 and its figure supplement.

The following data sets were generated

Article and author information

Author details

  1. Zhou Yu

    Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3213-4583
  2. Lauren E Surface

    Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States
    Competing interests
    No competing interests declared.
  3. Chong Yon Park

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  4. Max A Horlbeck

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3875-871X
  5. Gregory A Wyant

    Whitehead Institute for Biomedical Research, Cambridge, United States
    Competing interests
    No competing interests declared.
  6. Monther Abu-Remaileh

    Whitehead Institute for Biomedical Research, Cambridge, United States
    Competing interests
    No competing interests declared.
  7. Timothy R Peterson

    Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, United States
    Competing interests
    No competing interests declared.
  8. David M Sabatini

    Whitehead Institute for Biomedical Research, Cambridge, United States
    Competing interests
    No competing interests declared.
  9. Jonathan S Weissman

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2445-670X
  10. Erin K O'Shea

    Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States
    For correspondence
    osheae@hhmi.org
    Competing interests
    Erin K O'Shea, Chief Scientific Officer and a Vice President at the Howard Hughes Medical Institute, one of the three founding funders of eLife..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2649-1018

Funding

Howard Hughes Medical Institute

  • Zhou Yu
  • Lauren E Surface
  • Chong Yon Park
  • Max A Horlbeck
  • Gregory A Wyant
  • Monther Abu-Remaileh
  • David M Sabatini
  • Jonathan S Weissman
  • Erin K O'Shea

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Philip A Cole, Harvard Medical School, United States

Publication history

  1. Received: March 13, 2018
  2. Accepted: May 9, 2018
  3. Accepted Manuscript published: May 10, 2018 (version 1)
  4. Version of Record published: June 27, 2018 (version 2)

Copyright

© 2018, Yu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Zhou Yu
  2. Lauren E Surface
  3. Chong Yon Park
  4. Max A Horlbeck
  5. Gregory A Wyant
  6. Monther Abu-Remaileh
  7. Timothy R Peterson
  8. David M Sabatini
  9. Jonathan S Weissman
  10. Erin K O'Shea
(2018)
Identification of a transporter complex responsible for the cytosolic entry of nitrogen-containing-bisphosphonates
eLife 7:e36620.
https://doi.org/10.7554/eLife.36620
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