title: A putative role for the immunoproteasome in the maintenance of pluripotency in human embryonic stem cells.
abstract: The function of the proteasome is essential for maintenance of cellular homeostasis, and in pluripotent stem cells, this has been extended to the removal of nascent proteins in a manner that restricts differentiation. In this study, we show enhanced expression of genes encoding subunits of the 20S proteasome in human embryonic stem cells (hESCs) coupled to their downregulation as the cells progress into differentiation. The decrease in expression is particularly marked for the alternative catalytic subunits of the 20S proteasome variant known as the immunoproteasome indicating the possibility of a hitherto unknown function for this proteasome variant in pluripotent cells. The immunoproteasome is normally associated with antigen-presenting cells where it provides peptides of an appropriate length for antibody generation; however, our data suggest that it may be involved in maintaining the pluripotency in hESCs. Selective inhibition of two immunoproteasome subunits (PSMB9 and PSMB8) results in downregulation of cell surface and transcriptional markers that characterize the pluripotent state, subtle cell accumulation in G1 at the expense of S-phase, and upregulation of various markers characterizing the differentiated primitive and definitive lineages arising from hESC. Our data also support a different function for each of these two subunits in hESC that may be linked to their selectivity in driving proteasome-mediated degradation of cell cycle regulatory components and/or differentiation inducing factors.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Stuart P
authors.initials: SP
authors.lastname: Atkinson
authors.forename: Joseph
authors.initials: J
authors.lastname: Collin
authors.forename: Neganova
authors.initials: N
authors.lastname: Irina
authors.forename: George
authors.initials: G
authors.lastname: Anyfantis
authors.forename: Bo Kim
authors.initials: BK
authors.lastname: Kyung
authors.forename: Majlinda
authors.initials: M
authors.lastname: Lako
authors.forename: Lyle
authors.initials: L
authors.lastname: Armstrong
mesh_terms: D015153:Blotting, Western; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C071313:LMP-2 protein; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex