Identification of a transporter complex responsible for the cytosolic entry of nitrogen-containing bisphosphonates.
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 (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.
|Year of Publication
2018 05 10
|PubMed Central ID
T32 GM007287 / GM / NIGMS NIH HHS / United States
T32 GM007618 / GM / NIGMS NIH HHS / United States
HHMI / Howard Hughes Medical Institute / United States
R01 AR073017 / AR / NIAMS NIH HHS / United States
R00 AG047255 / AG / NIA NIH HHS / United States
K99 AG047255 / AG / NIA NIH HHS / United States