Protein S-nitrosylation regulates proteostasis and viability of hematopoietic stem cell during regeneration

Hematopoietic stem cells (HSCs) regenerate blood cells upon hematopoietic injuries. During homeostasis, HSCs are maintained in a low reactive oxygen species (ROS) state to prevent exhaustion. However, the role of nitric oxide (NO) in controlling HSC regeneration is still unclear. Here, we find increased NO during HSC regeneration with an accumulation of protein aggregation. S-nitrosoglutathione reductase (GSNOR)-deleted HSCs exhibit a reduced reconstitution capacity and loss of self-renewal after chemotherapeutic injury, which is resolved by inhibition of NO synthesis. Deletion of GSNOR enhances protein S-nitrosylation, resulting in an accumulation of protein aggregation and activation of unfolded protein response (UPR). Treatment of taurocholic acid (TCA), a chemical chaperone, rescues the regeneration defect of Gsnor(−/−) HSCs after 5-fluorouracil (5-FU) treatment. Deletion of C/EBP homologous protein (Chop) restores the reconstitution capacity of Gsnor(−/−) HSCs. These findings establish a link between S-nitrosylation and protein aggregation in HSC in the context of blood regeneration.