RHEB is normally maintained at low levels in HSCs via HRD1/SEL1L (ERAD), which targets it for proteasomal degradation, thereby keeping mTORC activation low. When Sel1L is genetically deleted, RHEB is stabilized and mTORC1 is activated, leading to HSC loss of quiescence. ER, endoplasmic reticulum; KO, knockout; WT, wild-type.