PERK signaling maintains hematopoietic stem cell pool integrity under endoplasmic reticulum stress by promoting proliferation Available to Purchase

• PERK is not essential for steady-state hematopoiesis but is crucial for HSC dysfunction under ER stress caused by ERAD deficiency.

• Upon ERAD deficiency, PERK is activated to promote mTOR signaling and HSC hyperproliferation, thereby depleting damaged HSCs.

The integrity of the hematopoietic stem cell (HSC) pool depends on effective long-term self-renewal and the timely elimination of damaged or differentiation-prone HSCs. Although the protein kinase R–like endoplasmic reticulum kinase (PERK) branch of the unfolded protein response has been shown to initiate proapoptotic signaling in response to endoplasmic reticulum (ER) stress in vitro, its role in regulating the HSC fate in vivo remains incompletely understood. Here, we demonstrated that PERK is dispensable for steady-state hematopoiesis and HSC self-renewal under homeostatic conditions. However, under ER stress induced by the disruption of ER-associated degradation (ERAD) through knockout of key components, such as Sel1L or Hrd1, PERK becomes activated and drives HSC proliferation and depletion. Notably, deletion of PERK or expression of a kinase-dead PERK mutant significantly rescued the HSC defects caused by Sel1L or Hrd1 loss. Mechanistically, an ERAD deficiency did not lead to increased HSC apoptosis or elevated reactive oxygen species, and PERK knockout had minimal impact on HSC apoptosis. Instead, PERK activation promoted aberrant mTOR (mammalian target of rapamycin) signaling and HSC hyperproliferation, ultimately compromising self-renewal capacity. This PERK-driven elimination of stressed HSCs may function as a protective mechanism to maintain the overall HSC pool integrity. Collectively, our findings reveal a previously unrecognized, proliferative, and apoptosis-independent role for PERK in regulating HSC fate under ER stress, highlighting a novel mechanism for preserving HSC homeostasis.