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

Nitrogen-containing-bisphosphonates (N-BPs) are widely prescribed to treat
osteoporosis and other bone-related diseases. Although previous studies
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.