title: The Key Regulator for Language and Speech Development, FOXP2, is a Novel Substrate for SUMOylation.
abstract: Transcription factor forkhead box protein P2 (FOXP2) plays an essential role in the development of language and speech. However, the transcriptional activity of FOXP2 regulated by the post-translational modifications remains unknown. Here, we demonstrated that FOXP2 is clearly defined as a SUMO target protein at the cellular levels as FOXP2 is covalently modified by both SUMO1 and SUMO3. Furthermore, SUMOylation of FOXP2 was significantly decreased by SENP2 (a specific SUMOylation protease). We further showed that FOXP2 is selectively SUMOylated in vivo on a phylogenetically conserved lysine 674 but the SUMOylation does not alter subcellular localization and stability of FOXP2. Interestingly, we observed that human etiological FOXP2 R553H mutation robustly reduces its SUMOylation potential as compared to wild-type FOXP2. In addition, the acidic residues downstream the core SUMO motif on FOXP2 are required for its full SUMOylation capacity. Finally, our functional analysis using reporter gene assays showed that SUMOylation may modulate transcriptional activity of FOXP2 in regulating downstream target genes (DISC1, SRPX2, and MiR200c). Altogether, we provide the first evidence that FOXP2 is a substrate for SUMOylation and SUMOylation of FOXP2 plays a functional role in regulating its transcriptional activity.
authors.affiliation: Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia 30404.
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Meredith
authors.affiliation: Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia 30404.
authors.forename: Chiung-Min
authors.initials: CM
authors.lastname: Wang
authors.affiliation: Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia 30404.
authors.forename: Leticia
authors.initials: L
authors.lastname: Nascimento
authors.affiliation: Department of Genetics and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Runhua
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Genetics and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Lizhong
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia 30404.
authors.forename: Wei-Hsiung
authors.initials: WH
authors.lastname: Yang
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D016384:Consensus Sequence; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D008969:Molecular Sequence Data; D017354:Point Mutation; D055550:Protein Stability; D025842:SUMO-1 Protein / Q000378:metabolism; D058207:Sumoylation; D015533:Transcriptional Activation
chemical_list: C465448:FOXP2 protein, human; D051858:Forkhead Transcription Factors; D025842:SUMO-1 Protein
keywords: FOXP2; SUMOylation; TRANSCRIPTIONAL ACTIVITY