Identification of a Transporter Complex Responsible for the Cytosolic Entry of Nitrogen-containing Bisphosphonates

Overview

Journal Elife

Specialty Biology

Date 2018 May 11

PMID 29745899

Citations 22

Authors

Zhou Yu

Lauren E Surface

Chong Yon Park

Max A Horlbeck

Gregory A Wyant

Monther Abu-Remaileh

Timothy R Peterson

David M Sabatini

Jonathan S Weissman

Erin K OShea

Affiliations

Soon will be listed here.

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 (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.

Citing Articles

Geranylgeranyl diphosphate synthase inhibition impairs osteoclast differentiation, morphology, and resorptive activity.

Muehlebach M, Haney S, Chhonker Y, Rashid M, Murry D, Talmon G JBMR Plus. 2024; 9(1):ziae133.

PMID: 39697524 PMC: 11653010. DOI: 10.1093/jbmrpl/ziae133.

Unsynchronized butyrophilin molecules dictate cancer cell evasion of Vγ9Vδ2 T-cell killing.

Wu Z, Lamao Q, Gu M, Jin X, Liu Y, Tian F Cell Mol Immunol. 2024; 21(4):362-373.

PMID: 38374404 PMC: 10978999. DOI: 10.1038/s41423-024-01135-z.

ADAM19 cleaves the PTH receptor and associates with brachydactyly type E.

Aydin A, Klenk C, Nemec K, Isbilir A, Martin L, Zauber H Life Sci Alliance. 2024; 7(4).

PMID: 38331475 PMC: 10853454. DOI: 10.26508/lsa.202302400.

Mechanosensitive channels TMEM63A and TMEM63B mediate lung inflation-induced surfactant secretion.

Chen G, Li J, Chen X, Liu J, Zhang Q, Liu J J Clin Invest. 2023; 134(5).

PMID: 38127458 PMC: 10904053. DOI: 10.1172/JCI174508.

CRISPR screens decode cancer cell pathways that trigger γδ T cell detection.

Mamedov M, Vedova S, Freimer J, Sahu A, Ramesh A, Arce M Nature. 2023; 621(7977):188-195.

PMID: 37648854 PMC: 11003766. DOI: 10.1038/s41586-023-06482-x.

References

Pan C, Chen S, Jun H, Lin S, Mansfield B, Chou J . SLC37A1 and SLC37A2 are phosphate-linked, glucose-6-phosphate antiporters. PLoS One. 2011; 6(9):e23157. PMC: 3176764. DOI: 10.1371/journal.pone.0023157. View

Thompson K, Rogers M, Coxon F, Crockett J . Cytosolic entry of bisphosphonate drugs requires acidification of vesicles after fluid-phase endocytosis. Mol Pharmacol. 2006; 69(5):1624-32. DOI: 10.1124/mol.105.020776. View

Liu X, Fagotto F . A method to separate nuclear, cytosolic, and membrane-associated signaling molecules in cultured cells. Sci Signal. 2011; 4(203):pl2. DOI: 10.1126/scisignal.2002373. View

Luckman S, Coxon F, Ebetino F, Russell R, Rogers M . Heterocycle-containing bisphosphonates cause apoptosis and inhibit bone resorption by preventing protein prenylation: evidence from structure-activity relationships in J774 macrophages. J Bone Miner Res. 1998; 13(11):1668-78. DOI: 10.1359/jbmr.1998.13.11.1668. View

Wyant G, Abu-Remaileh M, Wolfson R, Chen W, Freinkman E, Danai L . mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient. Cell. 2017; 171(3):642-654.e12. PMC: 5704964. DOI: 10.1016/j.cell.2017.09.046. View

Drake M, Clarke B, Khosla S . Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc. 2008; 83(9):1032-45. PMC: 2667901. DOI: 10.4065/83.9.1032. View

Roca-Ayats N, Balcells S, Garcia-Giralt N, Falco-Mascaro M, Martinez-Gil N, Abril J . GGPS1 Mutation and Atypical Femoral Fractures with Bisphosphonates. N Engl J Med. 2017; 376(18):1794-1795. DOI: 10.1056/NEJMc1612804. View

Ran F, Hsu P, Wright J, Agarwala V, Scott D, Zhang F . Genome engineering using the CRISPR-Cas9 system. Nat Protoc. 2013; 8(11):2281-2308. PMC: 3969860. DOI: 10.1038/nprot.2013.143. View

Fisher J, Rodan G, Reszka A . In vivo effects of bisphosphonates on the osteoclast mevalonate pathway. Endocrinology. 2000; 141(12):4793-6. DOI: 10.1210/endo.141.12.7921. View

10.

Huttlin E, Bruckner R, Paulo J, Cannon J, Ting L, Baltier K . Architecture of the human interactome defines protein communities and disease networks. Nature. 2017; 545(7655):505-509. PMC: 5531611. DOI: 10.1038/nature22366. View

11.

Collin-Osdoby P, Osdoby P . RANKL-mediated osteoclast formation from murine RAW 264.7 cells. Methods Mol Biol. 2011; 816:187-202. DOI: 10.1007/978-1-61779-415-5_13. View

12.

Martin D, Piulachs M, Cunillera N, Ferrer A, Belles X . Mitochondrial targeting of farnesyl diphosphate synthase is a widespread phenomenon in eukaryotes. Biochim Biophys Acta. 2007; 1773(3):419-26. DOI: 10.1016/j.bbamcr.2006.11.015. View

13.

Ding X, Chen Y, Han L, Qiu W, Gu X, Zhang H . Apoptosis related protein 3 is a lysosomal membrane protein. Biochem Biophys Res Commun. 2015; 460(4):915-22. DOI: 10.1016/j.bbrc.2015.03.127. View

14.

Makrides V, Camargo S, Verrey F . Transport of amino acids in the kidney. Compr Physiol. 2014; 4(1):367-403. DOI: 10.1002/cphy.c130028. View

15.

Dunford J, Thompson K, Coxon F, Luckman S, Hahn F, Poulter C . Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther. 2001; 296(2):235-42. View

16.

van Beek E, Pieterman E, Cohen L, Lowik C, Papapoulos S . Farnesyl pyrophosphate synthase is the molecular target of nitrogen-containing bisphosphonates. Biochem Biophys Res Commun. 1999; 264(1):108-11. DOI: 10.1006/bbrc.1999.1499. View

17.

Kampmann M, Bassik M, Weissman J . Integrated platform for genome-wide screening and construction of high-density genetic interaction maps in mammalian cells. Proc Natl Acad Sci U S A. 2013; 110(25):E2317-26. PMC: 3690882. DOI: 10.1073/pnas.1307002110. View

18.

Hughes D, Wright K, Uy H, Sasaki A, Yoneda T, Roodman G . Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J Bone Miner Res. 1995; 10(10):1478-87. DOI: 10.1002/jbmr.5650101008. View

19.

Luckman S, Hughes D, Coxon F, Graham R, Russell G, Rogers M . Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res. 1998; 13(4):581-9. DOI: 10.1359/jbmr.1998.13.4.581. View

20.

Jost M, Chen Y, Gilbert L, Horlbeck M, Krenning L, Menchon G . Combined CRISPRi/a-Based Chemical Genetic Screens Reveal that Rigosertib Is a Microtubule-Destabilizing Agent. Mol Cell. 2017; 68(1):210-223.e6. PMC: 5640507. DOI: 10.1016/j.molcel.2017.09.012. View