Elevated endocytic trafficking mediated by GPRASP2 maintains HSC fidelity.
Endolysosomal trafficking supports cellular homeostasis through coordinated regulation of extrinsic signaling inputs. Hematopoietic stem cell (HSC) function requires a tightly regulated balance between quiescence for long-term preservation and rapid activation for blood production. Although lysosomal regulation of metabolism and quiescence has been linked to stem cell maintenance, the contribution of endocytic routing to lysosomal function remains incompletely understood. Here, we show that quiescent HSCs rely on elevated endocytosis to maintain self-renewal. This activity is mediated in part by GPRASP2, a post-endosomal sorting protein. HSCs enriched in GPRASP2 are functionally dormant yet molecularly primed for activation however, in response to proliferative cues, dormant HSCs exhibit reduced signaling and proliferation. Disruption of GPRASP2-mediated endocytosis induces rapid proliferation and increased expression of signaling constituents, consistent with a model in which elevated endocytosis attenuates signaling through receptor internalization. Thus, we identify endocytosis as a mechanism by which HSCs limit functional exhaustion arising from chronic activation.