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

Haematologica. 2023 Sep 1;108(9):2410-2421. doi: 10.3324/haematol.2022.282224.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA-Binding Proteins* / genetics
  • DNA-Binding Proteins* / metabolism
  • Hematopoiesis* / genetics
  • Hematopoiesis* / physiology
  • Hematopoietic Stem Cells* / metabolism
  • Mice
  • Signal Transduction

Substances

  • Paxip1 protein, mouse
  • DNA-Binding Proteins

Grants and funding

Funding: This work is supported by the grants to HZ from the National Key R&D Program of China (2022YFA1103200), the National Natural Science Foundation of China (82230007), and the Hubei Provincial Natural Science Fund for Creative Research Groups (2021CFA003). This work is also supported by the grants to RY from the National Natural Science Foundation of China (82200188), and the Special Fund of China Postdoctoral Science Foundation (2022TQ0238). This work is also supported by the Medical Science Advancement Program (Basic Medical Sciences) of Wuhan University (TFJC2018005 to HZ), and by the Fundamental Research Funds for the Central Universities (2042021kf0225 to HZ).