title: The language-related transcription factor FOXP2 is post-translationally modified with small ubiquitin-like modifiers.
abstract: Mutations affecting the transcription factor FOXP2 cause a rare form of severe speech and language disorder. Although it is clear that sufficient FOXP2 expression is crucial for normal brain development, little is known about how this transcription factor is regulated. To investigate post-translational mechanisms for FOXP2 regulation, we searched for protein interaction partners of FOXP2, and identified members of the PIAS family as novel FOXP2 interactors. PIAS proteins mediate post-translational modification of a range of target proteins with small ubiquitin-like modifiers (SUMOs). We found that FOXP2 can be modified with all three human SUMO proteins and that PIAS1 promotes this process. An aetiological FOXP2 mutation found in a family with speech and language disorder markedly reduced FOXP2 SUMOylation. We demonstrate that FOXP2 is SUMOylated at a single major site, which is conserved in all FOXP2 vertebrate orthologues and in the paralogues FOXP1 and FOXP4. Abolishing this site did not lead to detectable changes in FOXP2 subcellular localization, stability, dimerization or transcriptional repression in cellular assays, but the conservation of this site suggests a potential role for SUMOylation in regulating FOXP2 activity in vivo.
authors: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Wundtlaan 1, 6525 XD, Nijmegen, The Netherlands.
authors: Sara B
authors: SB
authors: Estruch
authors: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Wundtlaan 1, 6525 XD, Nijmegen, The Netherlands.
authors: Sarah A
authors: SA
authors: Graham
authors: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Wundtlaan 1, 6525 XD, Nijmegen, The Netherlands.
authors: Pelagia
authors: P
authors: Deriziotis
authors: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Wundtlaan 1, 6525 XD, Nijmegen, The Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6525 EN, Nijmegen, The Netherlands.
authors: Simon E
authors: SE
authors: Fisher
mesh_terms: D000595:Amino Acid Sequence; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007802:Language; D008239:Lysine / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D011485:Protein Binding; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D058207:Sumoylation; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: C465448:FOXP2 protein, human; D051858:Forkhead Transcription Factors; D050505:Mutant Proteins; D050828:Protein Inhibitors of Activated STAT; D025841:Small Ubiquitin-Related Modifier Proteins; D044767:Ubiquitin-Protein Ligases; D008239:Lysine