Loss of Tars induces proteostasis stress and drives HSPC exhaustion through mTORC1 activation.

Hematopoietic stem and progenitor cells (HSPCs) rely on tightly regulated proteostasis to preserve their self-renewal and differentiation potential throughout life. However, how proteostasis stress induced by translational dysregulation affects HSPC homeostasis remains poorly understood. Here, we found that knockout of the cytoplasmic threonyl-tRNA synthetase (Tars), which is a component of the translation machinery, caused HSPC exhaustion and definitive, but not primitive, hematopoiesis defects in zebrafish. Similarly, TARS functional deficiency resulted in human CD34⁺ HSC exhaustion and a decrease in colony-forming unit-granulocyte, macrophage (CFU-GM) and colony-forming unit-macrophage (CFU-M) numbers while sparing burst-forming unit-erythroid (BFU-E) numbers in vitro. Functional rescue experiments demonstrated that the enzymatic activity of Tars is indispensable for HSPC maintenance and definitive hematopoiesis. Interestingly, these phenotypes occurred prior to the apparent decrease in global protein translation and were independent of global translation inhibition, hinting that these defective HSPCs were eliminated by an unknown mechanism. Transcriptomic and proteomic profiling revealed that Tars deletion caused widespread proteomic reprogramming and mTORC1 signaling activation, whereas pharmacological or genetic inhibition of mTORC1 partially rescued HSPC exhaustion in tars^-/- embryos. These findings uncover a link between translational machinery integrity, mTORC1 signaling, and HSPC fate determination, providing critical insight into how proteostasis stress is sensed and resolved to maintain hematopoietic homeostasis.