title: Nat1 promotes translation of specific proteins that induce differentiation of mouse embryonic stem cells.
abstract: Novel APOBEC1 target 1 (Nat1) (also known as "p97," "Dap5," and "Eif4g2") is a ubiquitously expressed cytoplasmic protein that is homologous to the C-terminal two thirds of eukaryotic translation initiation factor 4G (Eif4g1). We previously showed that Nat1-null mouse embryonic stem cells (mES cells) are resistant to differentiation. In the current study, we found that NAT1 and eIF4G1 share many binding proteins, such as the eukaryotic translation initiation factors eIF3 and eIF4A and ribosomal proteins. However, NAT1 did not bind to eIF4E or poly(A)-binding proteins, which are critical for cap-dependent translation initiation. In contrast, compared with eIF4G1, NAT1 preferentially interacted with eIF2, fragile X mental retardation proteins (FMR), and related proteins and especially with members of the proline-rich and coiled-coil-containing protein 2 (PRRC2) family. We also found that Nat1-null mES cells possess a transcriptional profile similar, although not identical, to the ground state, which is established in wild-type mES cells when treated with inhibitors of the ERK and glycogen synthase kinase 3 (GSK3) signaling pathways. In Nat1-null mES cells, the ERK pathway is suppressed even without inhibitors. Ribosome profiling revealed that translation of mitogen-activated protein kinase kinase kinase 3 (Map3k3) and son of sevenless homolog 1 (Sos1) is suppressed in the absence of Nat1 Forced expression of Map3k3 induced differentiation of Nat1-null mES cells. These data collectively show that Nat1 is involved in the translation of proteins that are required for cell differentiation.
authors.affiliation: Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Hayami
authors.initials: H
authors.lastname: Sugiyama
authors.affiliation: Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.|Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.|Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto 606-8501, Japan.|Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo 100-0004, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Mio
authors.initials: M
authors.lastname: Iwasaki
authors.affiliation: Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Narita
authors.affiliation: Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.
authors.forename: Tim A
authors.initials: TA
authors.lastname: Rand
authors.affiliation: Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.|Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto 606-8501, Japan.|Japan Science and Technology Agency (JST)-CREST, Saitama 332-0012, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan; yamanaka@cira.kyoto-u.ac.jp.|Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamanaka
mesh_terms: D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism*; D048748:MAP Kinase Kinase Kinase 3 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000378:metabolism* / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D014176:Protein Biosynthesis / Q000502:physiology*; D012270:Ribosomes / Q000378:metabolism; D020837:SOS1 Protein / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D039603:Eukaryotic Initiation Factor-4G; D007527:Isoenzymes; D020837:SOS1 Protein; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; D048748:MAP Kinase Kinase Kinase 3; D038362:Glycogen Synthase Kinase 3
keywords: Eif4g1; Map3k3; Nat1; mouse embryonic stem cells; translation control