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

Abstract

Embryonic stem cells are able to replicate continuously in the absence of senescence and, therefore, are immortal in culture1,2. While genome stability is central for survival of stem cells; proteome stability may play an equally important role in stem cell identity and function. Additionally, with the asymmetric divisions invoked by stem cells, the passage of damaged proteins to daughter cells could potentially destroy the resulting lineage of cells. We hypothesized that stem cells have an increased proteostasis ability compared to their differentiated counterparts and asked whether proteasome activity differed among human embryonic stem cells (hESCs). Notably, hESC populations exhibit a high proteasome activity that is correlated with increased levels of the 19S proteasome subunit PSMD11/RPN-63–5 and a corresponding increased assembly of the 26S/30S proteasome. Ectopic expression of PSMD11 is sufficient to increase proteasome assembly and activity. Proteasome inhibition affects pluripotency of hESCs inducing differentiation towards specific cell lineages. FOXO4, an insulin/IGF-1 responsive transcription factor associated with long lifespan in invertebrates6,7, regulates proteasome activity by modulating the expression of PSMD11 in hESCs. Our results establish a novel regulation of proteostasis in hESCs that links longevity and stress resistance in invertebrates with hESC function and identity.

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

“…Moreover, pathogenesis of neurodegenerative disorders such as Parkinson's, Alzheimer's, or Huntington's disease is generally related to an abnormal ubiquitin‐proteasome mechanism as either a primary cause or secondary consequence (Ciechanover & Brundin, 2003; Kikis et al ., 2010; Webb & Brunet, 2014). FOXOs act on both the upregulation of ubiquitin ligases and by controlling the composition of the proteasome (Bodine et al ., 2001; Sandri et al ., 2004, 2006; Stitt et al ., 2004; Vilchez et al ., 2012). However, the direct effect of FOXO‐mediated proteostasis in mammals remains to be understood.…”

“…But FOXOs can also affect the composition of the proteasome. In particular, FOXO4 has been shown to be required for the expression of the proteasome component PSMD11 in human embryonic stem cells (Vilchez et al ., 2012). …”

The role of protein clearance mechanisms in organismal ageing and age-related diseases

“…ESCs do not undergo replicative senescence-a capacity that necessarily demands avoidance of any imbalance in proteostasis that would otherwise compromise its function during replication. Accordingly, human (hESCs) and mouse ESCs (mESCs) exhibit high proteasome activity compared to their differentiated counterparts and this activity does not differ depending on the passage number 64 . Increased proteasome activity is correlated with enhanced levels of the 19S subunit PSMD11/Rpn6 (refs 64-66), which is essential for the activity of the 26S/30S proteasome and stabilizes the otherwise weak interaction between the 20S core and the 19S cap 64,67 .…”

“…The underlying mechanisms for this selectivity might be that malignant cells show greater sensitivity to the cytotoxic effects of proteasome inhibition than non-cancer cells 39 . Likewise, immortal hESCs are more sensitive to proteasome inhibition than their differentiated counterparts 64 . In contrast, increased autophagy plays an important role in oncogenic suppression since its inhibition increases the frequency of tumours in mice 21 .…”

“…NATURE COMMUNICATIONS | DOI: 10.1038/ncomms6659 REVIEW immortal hESCs, increased proteasome activity, rpn6 expression and longevity are modulated by DAF-16 in these long-lived animals 64,173 . Interestingly, DNA damage in C. elegans germ cells induces a systemic response that protects somatic tissues by increasing their proteasome activity 174 .…”