Facilitative lysosomal transport of bile acids alleviates ER stress in mouse hematopoietic precursors
| Autor: | Sreenath Nair, Avinash K. Persaud, Xiaolin Cheng, Debasis Nayak, Brenna Weadick, Craig A. McElroy, Radhika Raj, Muruganandan Shanmugam, Rajgopal Govindarajan, Sue E. Knoblaugh, Fazlur Rahman |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Lysosomal transport Cell Survival Taurine Science General Physics and Astronomy Apoptosis Bone Marrow Cells Pathogenesis Nucleoside Transport Proteins Endoplasmic Reticulum General Biochemistry Genetics and Molecular Biology Article Bile Acids and Salts Taurochenodeoxycholic Acid 03 medical and health sciences Stress signalling Mice 0302 clinical medicine Erythroid Cells hemic and lymphatic diseases Animals Metabolomics Progenitor cell chemistry.chemical_classification Reactive oxygen species Multidisciplinary Endoplasmic reticulum Haematopoietic stem cells Hematopoietic Stem Cell Transplantation Biological Transport Cell Differentiation General Chemistry Hydrogen-Ion Concentration Endoplasmic Reticulum Stress Hematopoietic Stem Cells Cell biology Haematopoiesis 030104 developmental biology chemistry Unfolded protein response Erythropoiesis Chemical chaperone Lysosomes 030217 neurology & neurosurgery |
| Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-18 (2021) |
| ISSN: | 2041-1723 |
| Popis: | Mutations in human equilibrative nucleoside transporter 3 (ENT3) encoded by SLC29A3 results in anemia and erythroid hypoplasia, suggesting that ENT3 may regulate erythropoiesis. Here, we demonstrate that lysosomal ENT3 transport of taurine-conjugated bile acids (TBA) facilitates TBA chemical chaperone function and alleviates endoplasmic reticulum (ER) stress in expanding mouse hematopoietic stem and progenitor cells (HSPCs). Slc29a3−/− HSPCs accumulate less TBA despite elevated levels of TBA in Slc29a3−/− mouse plasma and have elevated basal ER stress, reactive oxygen species (ROS), and radiation-induced apoptosis. Reintroduction of ENT3 allows for increased accumulation of TBA into HSPCs, which results in TBA-mediated alleviation of ER stress and erythroid apoptosis. Transplanting TBA-preconditioned HSPCs expressing ENT3 into Slc29a3−/− mice increase bone marrow repopulation capacity and erythroid pool size and prevent early mortalities. Together, these findings suggest a putative role for a facilitative lysosomal transporter in the bile acid regulation of ER stress in mouse HSPCs which may have implications in erythroid biology, the treatment of anemia observed in ENT3-mutated human genetic disorders, and nucleoside analog drug therapy. Mutations in ENT3, encoded by SLC29A3, result in anaemia and erythroid hypoplasia, suggesting roles in erythropoiesis. Here the authors show that ENT3 acts as a lysosomal bile acid transporter, and mutation compromises taurine conjugated bile acid transport in erythroid progenitors leading to ER stress, and anaemia. |
| Databáze: | OpenAIRE |
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