title: A CUL-2 ubiquitin ligase containing three FEM proteins degrades TRA-1 to regulate C. elegans sex determination.
abstract: In Caenorhabditis elegans, the Gli-family transcription factor TRA-1 is the terminal effector of the sex-determination pathway. TRA-1 activity inhibits male development and allows female fates. Genetic studies have indicated that TRA-1 is negatively regulated by the fem-1, fem-2, and fem-3 genes. However, the mechanism of this regulation has not been understood. Here, we present data that TRA-1 is regulated by degradation mediated by a CUL-2-based ubiquitin ligase complex that contains FEM-1 as the substrate-recognition subunit, and FEM-2 and FEM-3 as cofactors. CUL-2 physically associates with both FEM-1 and TRA-1 in vivo, and cul-2 mutant males share feminization phenotypes with fem mutants. CUL-2 and the FEM proteins negatively regulate TRA-1 protein levels in C. elegans. When expressed in human cells, the FEM proteins interact with human CUL2 and induce the proteasome-dependent degradation of TRA-1. This work demonstrates that the terminal step in C. elegans sex determination is controlled by ubiquitin-mediated proteolysis.
authors.affiliation: Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA.
authors.forename: Natalia G
authors.initials: NG
authors.lastname: Starostina
authors.forename: Jae-min
authors.initials: JM
authors.lastname: Lim
authors.forename: Mara
authors.initials: M
authors.lastname: Schvarzstein
authors.forename: Lance
authors.initials: L
authors.lastname: Wells
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Spence
authors.forename: Edward T
authors.initials: ET
authors.lastname: Kipreos
mesh_terms: D000595:Amino Acid Sequence; D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D044842:Cullin Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D012734:Disorders of Sex Development; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D019849:Sex Determination Processes; D013379:Substrate Specificity; D014157:Transcription Factors / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; D044842:Cullin Proteins; D004268:DNA-Binding Proteins; C115306:FEM-1 protein, C elegans; D014157:Transcription Factors; D025801:Ubiquitin; C491027:cul-2 proteins, C elegans; C075059:fem-3 protein, C elegans; C121025:tra-1 protein, C elegans; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D044767:Ubiquitin-Protein Ligases; C097435:Fem-2 protein, C elegans; D010749:Phosphoprotein Phosphatases; D046988:Proteasome Endopeptidase Complex