Correa-Vázquez, Juan F.Juárez-Vicente, FranciscoGarcía-Gutiérrez, PabloBarysch, Sina V.Melchior, FraukeGarcía-Domínguez, Mario2022-09-022022-09-022021-03-22Correa-Vázquez JF, Juárez-Vicente F, García-Gutiérrez P, Barysch SV, Melchior F, García-Domínguez M. The Sumo proteome of proliferating and neuronal-differentiating cells reveals Utf1 among key Sumo targets involved in neurogenesis. Cell Death Dis. 2021 Mar 22;12(4):305http://hdl.handle.net/10668/3990Post-translational modification by covalent attachment of the Small ubiquitin-like modifier (Sumo) polypeptide regulates a multitude of processes in vertebrates. Despite demonstrated roles of Sumo in the development and function of the nervous system, the identification of key factors displaying a sumoylation-dependent activity during neurogenesis remains elusive. Through a SILAC (stable isotope labeling by/with amino acids in cell culture)-based proteomic approach, we have identified the Sumo proteome of the model cell line P19 under proliferation and neuronal differentiation conditions. More than 300 proteins were identified as putative Sumo targets differentially associated with one or the other condition. A group of proteins of interest were validated and investigated in functional studies. Among these, Utf1 was revealed as a new Sumo target. Gain-of-function experiments demonstrated marked differences between the effects on neurogenesis of overexpressing wild-type and sumoylation mutant versions of the selected proteins. While sumoylation of Prox1, Sall4a, Trim24, and Utf1 was associated with a positive effect on neurogenesis in P19 cells, sumoylation of Kctd15 was associated with a negative effect. Prox1, Sall4a, and Kctd15 were further analyzed in the vertebrate neural tube of living embryos, with similar results. Finally, a detailed analysis of Utf1 showed the sumoylation dependence of Utf1 function in controlling the expression of bivalent genes. Interestingly, this effect seems to rely on two mechanisms: sumoylation modulates binding of Utf1 to the chromatin and mediates recruitment of the messenger RNA-decapping enzyme Dcp1a through a conserved SIM (Sumo-interacting motif). Altogether, our results indicate that the combined sumoylation status of key proteins determines the proper progress of neurogenesis.enAtribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/ProteomeProteomaNeural tubeTubo neuralNeurogenesisNeurogénesisRNAARNAminoácidos, péptidos y proteínasAmino acids, peptides, and proteinsMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell DifferentiationMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Differentiation::NeurogenesisMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Nuclear ProteinsMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Protein Modification, Translational::Protein Processing, Post-TranslationalMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::ProteomeMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Ubiquitins::Small Ubiquitin-Related Modifier ProteinsMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Protein Modification, Translational::Protein Processing, Post-Translational::Ubiquitination::SumoylationMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Transcription Factors::Trans-ActivatorsMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Disciplines and Occupations::Natural Science Disciplines::Chemistry::Biochemistry::ProteomicsMedical Subject Headings::Anatomy::Embryonic Structures::Neural TubeMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Isotope LabelingMedical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell LineMedical Subject Headings::Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::RNA::RNA, MessengerMedical Subject Headings::Anatomy::Nervous SystemMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Culture Techniques::Cell Culture TechniquesMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Growth Processes::Cell ProliferationMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::PeptidesMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Amino AcidsMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebratesresearch article33753728Acceso abierto10.1038/s41419-021-03590-22041-4889PMC7985304