Facilitative lysosomal transport of bile acids alleviates ER stress in mouse hematopoietic precursors

Avinash K. Persaud, Sreenath Nair, Md Fazlur Rahman, Radhika Raj, Brenna Weadick, Debasis Nayak, Craig McElroy, Muruganandan Shanmugam, Sue Knoblaugh, Xiaolin Cheng and Rajgopal Govindarajan ()
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Avinash K. Persaud: Ohio State University
Sreenath Nair: Ohio State University
Md Fazlur Rahman: Ohio State University
Radhika Raj: Ohio State University
Brenna Weadick: Ohio State University
Debasis Nayak: Ohio State University
Craig McElroy: Ohio State University
Muruganandan Shanmugam: Ohio State University
Sue Knoblaugh: Ohio State University
Xiaolin Cheng: Ohio State University
Rajgopal Govindarajan: Ohio State University

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-21451-6

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