Bmi1 suppresses protein synthesis and promotes proteostasis in hematopoietic stem cells

The polycomb complex component Bmi1 promotes the maintenance of stem cells in multiple postnatal tissues, partly by negatively regulating the expression of p16(Ink4a) and p19(Arf), tumor suppressors associated with cellular senescence. However, deficiency for p16(Ink4a) and p19(Arf) only partially rescues the function of Bmi1-deficient stem cells. We conditionally deleted Bmi1 from adult hematopoietic cells and found that this slowly depleted hematopoietic stem cells (HSCs). Rather than inducing senescence, Bmi1 deficiency increased HSC division. The increased cell division was caused partly by increased Aristaless-related homeobox (ARX) transcription factor expression, which also increased ribosomal RNA expression. However, ARX deficiency did not rescue HSC depletion. Bmi1 deficiency also increased protein synthesis, protein aggregation, and protein ubiquitylation independent of its effects on cell division and p16(Ink4a), p19(Arf), and ARX expression. Bmi1 thus promotes HSC quiescence by negatively regulating ARX expression and promotes proteostasis by suppressing protein synthesis. This highlights a new connection between the regulation of stem cell maintenance and proteostasis. In this study, Burgess et al. conditionally deleted Bmi1 from adult hematopoietic cells and found that this slowly depleted hematopoietic stem cells (HSCs) and that, rather than inducing senescence, Bmi1 deficiency increased HSC division. Overall, they found that Bmi1 promotes HSC quiescence by negatively regulating ARX expression and promoting proteostasis by suppressing protein synthesis.