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...
| Main Authors: | , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications, Ltd
2020
|
| Subjects: | |
| Online Access: | https://hdl.handle.net/1721.1/124751 |
| _version_ | 1826206043786444800 |
|---|---|
| author | Wyant, Gregory A Abu-Remaileh, Monther Sabatini, David M. |
| author2 | Whitehead Institute for Biomedical Research |
| author_facet | Whitehead Institute for Biomedical Research Wyant, Gregory A Abu-Remaileh, Monther Sabatini, David M. |
| author_sort | Wyant, Gregory A |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T13:23:07Z |
| format | Article |
| id | mit-1721.1/124751 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T13:23:07Z |
| publishDate | 2020 |
| publisher | eLife Sciences Publications, Ltd |
| record_format | dspace |
| spelling | mit-1721.1/1247512022-09-28T13:48:55Z Identification of a transporter complex responsible for the cytosolic entry of nitrogen-containing bisphosphonates Wyant, Gregory A Abu-Remaileh, Monther Sabatini, David M. Whitehead Institute for Biomedical Research Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT General Biochemistry, Genetics and Molecular Biology General Immunology and Microbiology General Neuroscience General Medicine 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. 2020-04-21T12:15:25Z 2020-04-21T12:15:25Z 2018-05-10 2020-01-29T16:30:58Z Article http://purl.org/eprint/type/JournalArticle 2050-084X https://hdl.handle.net/1721.1/124751 Yu, Zhou , et al. “Identification of a transporter complex responsible for the cytosolic entry of nitrogen-containing bisphosphonates.” eLife 7 (2018): e36620 © 2018 The Author(s) en 10.7554/elife.36620 eLife Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf eLife Sciences Publications, Ltd eLife |
| spellingShingle | General Biochemistry, Genetics and Molecular Biology General Immunology and Microbiology General Neuroscience General Medicine Wyant, Gregory A Abu-Remaileh, Monther Sabatini, David M. Identification of a transporter complex responsible for the cytosolic entry of nitrogen-containing bisphosphonates |
| title | Identification of a transporter complex responsible for the cytosolic entry of nitrogen-containing bisphosphonates |
| title_full | Identification of a transporter complex responsible for the cytosolic entry of nitrogen-containing bisphosphonates |
| title_fullStr | Identification of a transporter complex responsible for the cytosolic entry of nitrogen-containing bisphosphonates |
| title_full_unstemmed | Identification of a transporter complex responsible for the cytosolic entry of nitrogen-containing bisphosphonates |
| title_short | Identification of a transporter complex responsible for the cytosolic entry of nitrogen-containing bisphosphonates |
| title_sort | identification of a transporter complex responsible for the cytosolic entry of nitrogen containing bisphosphonates |
| topic | General Biochemistry, Genetics and Molecular Biology General Immunology and Microbiology General Neuroscience General Medicine |
| url | https://hdl.handle.net/1721.1/124751 |
| work_keys_str_mv | AT wyantgregorya identificationofatransportercomplexresponsibleforthecytosolicentryofnitrogencontainingbisphosphonates AT aburemailehmonther identificationofatransportercomplexresponsibleforthecytosolicentryofnitrogencontainingbisphosphonates AT sabatinidavidm identificationofatransportercomplexresponsibleforthecytosolicentryofnitrogencontainingbisphosphonates |