title: SUMOylation regulates the transcriptional repression activity of FOG-2 and its association with GATA-4.
abstract: Friend of GATA 2 (FOG-2), a co-factor of several GATA transcription factors (GATA-4, -5 and 6), is a critical regulator of coronary vessel formation and heart morphogenesis. Here we demonstrate that FOG-2 is SUMOylated and that this modification modulates its transcriptional activity. FOG-2 SUMOylation occurs at four lysine residues (K324, 471, 915, 955) [corrected]. Three of these residues are part of the characteristic SUMO consensus site (ψKXE), while K955 is found in the less frequent TKXE motif. Absence of SUMOylation did not affect FOG-2's nuclear localization. However, mutation of the FOG-2 SUMOylation sites, or de-SUMOylation, with SENP-1 or SENP-8 resulted in stronger transcriptional repression activity in both heterologous cells and cardiomyocytes. Conversely, increased FOG-2 SUMOylation by overexpression of SUMO-1 or expression of a SUMO-1-FOG-2 fusion protein rendered FOG-2 incapable of repressing GATA-4-mediated activation of the B-type natriuretic peptide (BNP) promoter. Moreover, we demonstrate both increased interaction between a FOG-2 SUMO mutant and GATA-4 and enhanced SUMOylation of wild-type FOG-2 by co-expression of GATA-4. These data suggest a new dynamics in which GATA-4 may alter the activity of FOG-2 by influencing its SUMOylation status.
authors.affiliation: Department of Medicine, St George Clinical School, University of New South Wales, Sydney, New South Wales, Australia. j.perdomo@unsw.edu.au
authors.forename: José
authors.initials: J
authors.lastname: Perdomo
authors.forename: Xing-Mai
authors.initials: XM
authors.lastname: Jiang
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Carter
authors.forename: Levon M
authors.initials: LM
authors.lastname: Khachigian
authors.forename: Beng H
authors.initials: BH
authors.lastname: Chong
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D058207:Sumoylation; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*; D016335:Zinc Fingers
chemical_list: D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D014157:Transcription Factors; C492170:Zfpm2 protein, mouse; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases; C477008:SENP8 protein, human; D008239:Lysine