title: Regulation of pluripotency and cellular reprogramming by the ubiquitin-proteasome system.
abstract: Although transcriptional regulation of stem cell pluripotency and differentiation has been extensively studied, only a small number of studies have addressed the roles for posttranslational modifications in these processes. A key mechanism of posttranslational modification is ubiquitination by the ubiquitin-proteasome system (UPS). Here, using shotgun proteomics, we map the ubiquitinated protein landscape during embryonic stem cell (ESC) differentiation and induced pluripotency. Moreover, using UPS-targeted RNAi screens, we identify additional regulators of pluripotency and differentiation. We focus on two of these proteins, the deubiquitinating enzyme Psmd14 and the E3 ligase Fbxw7, and characterize their importance in ESC pluripotency and cellular reprogramming. This global characterization of the UPS as a key regulator of stem cell pluripotency opens the way for future studies that focus on specific UPS enzymes or ubiquitinated substrates.
authors.affiliation: Howard Hughes Medical Institute and Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Buckley
authors.forename: Beatriz
authors.initials: B
authors.lastname: Aranda-Orgilles
authors.forename: Alexandros
authors.initials: A
authors.lastname: Strikoudis
authors.forename: Effie
authors.initials: E
authors.lastname: Apostolou
authors.forename: Evangelia
authors.initials: E
authors.lastname: Loizou
authors.forename: Kelly
authors.initials: K
authors.lastname: Moran-Crusio
authors.forename: Charles L
authors.initials: CL
authors.lastname: Farnsworth
authors.forename: Antonius A
authors.initials: AA
authors.lastname: Koller
authors.forename: Ramanuj
authors.initials: R
authors.lastname: Dasgupta
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Silva
authors.forename: Matthias
authors.initials: M
authors.lastname: Stadtfeld
authors.forename: Konrad
authors.initials: K
authors.lastname: Hochedlinger
authors.forename: Emily I
authors.initials: EI
authors.lastname: Chen
authors.forename: Iannis
authors.initials: I
authors.lastname: Aifantis
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D065150:Cellular Reprogramming / Q000235:genetics*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D044783:F-Box Proteins / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006207:Half-Life; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D055550:Protein Stability; D059748:Proteolysis; D020543:Proteome / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C550223:PSMD14 protein, mouse; D020543:Proteome; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D015534:Trans-Activators; D025801:Ubiquitin; D049452:Green Fluorescent Proteins; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex