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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiporters / genetics
  • Antiporters / metabolism*
  • Bone Density Conservation Agents / metabolism*
  • Cell Line
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Diphosphonates / metabolism*
  • Genetic Testing
  • Genome-Wide Association Study
  • Humans
  • Lysosomes / metabolism
  • Membrane Transport Proteins / metabolism*
  • Mice
  • Monosaccharide Transport Proteins / genetics
  • Monosaccharide Transport Proteins / metabolism*
  • Nitrogen / metabolism*


  • ATRAID protein, human
  • Antiporters
  • Bone Density Conservation Agents
  • Diphosphonates
  • Membrane Transport Proteins
  • Monosaccharide Transport Proteins
  • SLC37A4 protein, human
  • Nitrogen