Increased proteasome activity in human embryonic stem cells is regulated by PSMD11

Human embryonic stem cells (hESCs) are shown to have high 26S/30S proteasome activity owing to increased expression of the 19S proteasome subunit PSMD11; FOXO4 regulates proteasome activity in hESCs by modulating PSMD11 expression, and the high proteasome activity decreases after induced differentiation. Proteasome linked to stem cells' longevity Two manuscripts in this issue of Nature converge on the role of the proteasome in longevity and stem-cell function. The first establishes a possible mechanism to explain why the removal of proliferating germline cells in the roundworm Caenorhabditis elegans extends lifespan. Worms with the glp-1(e2141) mutation lack a germ line and reallocate resources to the soma, potentially freeing up resources to invest in lifespan extension. These mutants also have sixfold higher proteasome activity than their normal counterparts, as well as increased clearance of damaged proteins associated with raised expression of the rpn-6 subunit of the 19S proteasome and the FOXO transcription factor DAF-16. Ectopic expression of rpn-6 is sufficient to extend lifespan and to protect against proteotoxic stress, suggesting that rpn-6 is a candidate to correct deficiencies in age-related protein-homeostasis disorders. The second paper starts with the hypothesis that rapidly dividing stem cells have high proteasome activity to safeguard the integrity of the genome and proteome by removing damaged proteins. Human embryonic stem cells are shown to exhibit high 26S/30S proteasome activity that decreases on induced differentiation. The high proteasome activity is due to increased expression of the 19S subunit PSMD11/RPN-6 and the modulation of its expression by FOXO4, an insulin/IGF-1-responsive transcription factor and DAF-16 orthologue. Embryonic stem cells can replicate continuously in the absence of senescence and, therefore, are immortal in culture 1 , 2 . Although genome stability is essential for the survival of stem cells, proteome stability may have an equally important role in stem-cell identity and function. Furthermore, with the asymmetric divisions invoked by stem cells, the passage of damaged proteins to daughter cells could potentially destroy the resulting lineage of cells. Therefore, a firm understanding of how stem cells maintain their proteome is of central importance. Here we show that human embryonic stem cells (hESCs) exhibit high proteasome activity that is correlated with increased levels of the 19S proteasome subunit PS