title: Increased proteasome activity in human embryonic stem cells is regulated by PSMD11.
abstract: Embryonic stem cells can replicate continuously in the absence of senescence and, therefore, are immortal in culture. 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 PSMD11 (known as RPN-6 in Caenorhabditis elegans) and a corresponding increased assembly of the 26S/30S proteasome. Ectopic expression of PSMD11 is sufficient to increase proteasome assembly and activity. FOXO4, an insulin/insulin-like growth factor-I (IGF-I) responsive transcription factor associated with long lifespan in invertebrates, regulates proteasome activity by modulating the expression of PSMD11 in hESCs. Proteasome inhibition in hESCs affects the expression of pluripotency markers and the levels of specific markers of the distinct germ layers. Our results suggest a new regulation of proteostasis in hESCs that links longevity and stress resistance in invertebrates to hESC function and identity.
authors.affiliation: Howard Hughes Medical Institute, Glenn Center for Aging Research, Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: David
authors.initials: D
authors.lastname: Vilchez
authors.forename: Leah
authors.initials: L
authors.lastname: Boyer
authors.forename: Ianessa
authors.initials: I
authors.lastname: Morantte
authors.forename: Margaret
authors.initials: M
authors.lastname: Lutz
authors.forename: Carsten
authors.initials: C
authors.lastname: Merkwirth
authors.forename: Derek
authors.initials: D
authors.lastname: Joyce
authors.forename: Brian
authors.initials: B
authors.lastname: Spencer
authors.forename: Lesley
authors.initials: L
authors.lastname: Page
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: W Travis
authors.initials: WT
authors.lastname: Berggren
authors.forename: Fred H
authors.initials: FH
authors.lastname: Gage
authors.forename: Andrew
authors.initials: A
authors.lastname: Dillin
mesh_terms: D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D051858:Forkhead Transcription Factors; D057809:HEK293 Cells; D006801:Humans; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D021122:Protein Subunits / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D018797:Cell Cycle Proteins; C108803:FOXO4 protein, human; D051858:Forkhead Transcription Factors; D061988:Proteasome Inhibitors; D021122:Protein Subunits; D014157:Transcription Factors; C549955:PSMD11 protein, human; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease