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

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