title: Degringolade, a SUMO-targeted ubiquitin ligase, inhibits Hairy/Groucho-mediated repression.
abstract: Transcriptional cofactors are essential for proper embryonic development. One such cofactor in Drosophila, Degringolade (Dgrn), encodes a RING finger/E3 ubiquitin ligase. Dgrn and its mammalian ortholog RNF4 are SUMO-targeted ubiquitin ligases (STUbLs). STUbLs bind to SUMOylated proteins via their SUMO interaction motif (SIM) domains and facilitate substrate ubiquitylation. In this study, we show that Dgrn is a negative regulator of the repressor Hairy and its corepressor Groucho (Gro/transducin-like enhancer (TLE)) during embryonic segmentation and neurogenesis, as dgrn heterozygosity suppresses Hairy mutant phenotypes and embryonic lethality. Mechanistically Dgrn functions as a molecular selector: it targets Hairy for SUMO-independent ubiquitylation that inhibits the recruitment of its corepressor Gro, without affecting the recruitment of its other cofactors or the stability of Hairy. Concomitantly, Dgrn specifically targets SUMOylated Gro for sequestration and antagonizes Gro functions in vivo. Our findings suggest that by targeting SUMOylated Gro, Dgrn serves as a molecular switch that regulates cofactor recruitment and function during development. As Gro/TLE proteins are conserved universal corepressors, this may be a general paradigm used to regulate the Gro/TLE corepressors in other developmental processes.
authors.affiliation: Cancer and Vascular Biology Research Center, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Mona
authors.initials: M
authors.lastname: Abed
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Barry
authors.forename: Dorit
authors.initials: D
authors.lastname: Kenyagin
authors.forename: Bella
authors.initials: B
authors.lastname: Koltun
authors.forename: Taryn M
authors.initials: TM
authors.lastname: Phippen
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Delrow
authors.forename: Susan M
authors.initials: SM
authors.lastname: Parkhurst
authors.forename: Amir
authors.initials: A
authors.lastname: Orian
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors*; D004330:Drosophila / Q000254:growth & development*; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D058207:Sumoylation; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D029721:Drosophila Proteins; D012097:Repressor Proteins; D044767:Ubiquitin-Protein Ligases; C091023:gro protein, Drosophila; C489235:hairy protein, Drosophila; C558536:dgrn protein, Drosophila