title: Cell-fate determination by ubiquitin-dependent regulation of translation.
abstract: Metazoan development depends on the accurate execution of differentiation programs that allow pluripotent stem cells to adopt specific fates. Differentiation requires changes to chromatin architecture and transcriptional networks, yet whether other regulatory events support cell-fate determination is less well understood. Here we identify the ubiquitin ligase CUL3 in complex with its vertebrate-specific substrate adaptor KBTBD8 (CUL3(KBTBD8)) as an essential regulator of human and Xenopus tropicalis neural crest specification. CUL3(KBTBD8) monoubiquitylates NOLC1 and its paralogue TCOF1, the mutation of which underlies the neurocristopathy Treacher Collins syndrome. Ubiquitylation drives formation of a TCOF1-NOLC1 platform that connects RNA polymerase I with ribosome modification enzymes and remodels the translational program of differentiating cells in favour of neural crest specification. We conclude that ubiquitin-dependent regulation of translation is an important feature of cell-fate determination.
authors.affiliation: Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA.|Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.
authors.forename: Achim
authors.initials: A
authors.lastname: Werner
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Iwasaki
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.
authors.forename: Colleen A
authors.initials: CA
authors.lastname: McGourty
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.
authors.forename: Sofia
authors.initials: S
authors.lastname: Medina-Ruiz
authors.affiliation: Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA.|Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.
authors.forename: Nia
authors.initials: N
authors.lastname: Teerikorpi
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.
authors.forename: Indro
authors.initials: I
authors.lastname: Fedrigo
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.
authors.forename: Nicholas T
authors.initials: NT
authors.lastname: Ingolia
authors.affiliation: Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA.|Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Rape
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D044842:Cullin Proteins / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008342:Mandibulofacial Dysostosis / Q000235:genetics; D009432:Neural Crest / Q000166:cytology* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis; D040901:Proteomics; D012318:RNA Polymerase I / Q000378:metabolism; D012270:Ribosomes / Q000737:chemistry / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination; D014981:Xenopus
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C503645:CUL3 protein, human; D044842:Cullin Proteins; C000602103:KBTBD8 protein, human; C075564:NOLC1 protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; C105442:TCOF1 protein, human; D025801:Ubiquitin; D012318:RNA Polymerase I