Pax transactivation domain-interacting protein is required for preserving hematopoietic stem cell quiescence via regulating lysosomal activity.

Tong Zhang, Manman Cui, Yashu Li, Ying Cheng, Zhuying Gao, Jing Wang, Tiantian Zhang, Guoqiang Han, Rong Yin, Peipei Wang, Wen Tian, Weidong Liu, Jin Hu, Yuhua Wang, Zheming Liu, Haojian Zhang

Haematologica 2023 Sep 01

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Hematopoietic stem cells (HSC) maintain lifetime whole blood hematopoiesis through self-renewal and differentiation. In order to sustain HSC stemness, most HSC reside in a quiescence state, which is affected by diverse cellular stress and intracellular signal transduction. How HSC accommodate those challenges to preserve lifetime capacity remains elusive. Here we show that Pax transactivation domain-interacting protein (PTIP) is required for preserving HSC quiescence via regulating lysosomal activity. Using a genetic knockout mouse model to specifically delete Ptip in HSC, we find that loss of Ptip promotes HSC exiting quiescence, and results in functional exhaustion of HSC. Mechanistically, Ptip loss increases lysosomal degradative activity of HSC. Restraining lysosomal activity restores the quiescence and repopulation potency of Ptip-/- HSC. Additionally, PTIP interacts with SMAD2/3 and mediates transforming growth factor-β signaling-induced HSC quiescence. Overall, our work uncovers a key role of PTIP in sustaining HSC quiescence via regulating lysosomal activity.

Citation

Tong Zhang, Manman Cui, Yashu Li, Ying Cheng, Zhuying Gao, Jing Wang, Tiantian Zhang, Guoqiang Han, Rong Yin, Peipei Wang, Wen Tian, Weidong Liu, Jin Hu, Yuhua Wang, Zheming Liu, Haojian Zhang. Pax transactivation domain-interacting protein is required for preserving hematopoietic stem cell quiescence via regulating lysosomal activity. Haematologica. 2023 Sep 01;108(9):2410-2421