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.

De novotranscriptome sequencing to identify the sex-determination genes inHyriopsis schlegelii

“…Two gene families, Fem (feminization) and Tra, have been characterized in nematodes. 15,16) The activation of Tra-1 (transformer 1) determines female fate via the suppression of male development genes, while Tra-2 (transformer 2) controls the activity of Tra-1 via the inhibition of Fem genes. 15) However, the sex-determination regulatory factors and signal pathways in freshwater bivalves have not been characterized.…”

“…Among the 41 GO classification functional groups, "cell" represented the largest term (4542), followed by "cellular process" (3337) and "binding" (2819). We identified categories involving reproduction, such as "reproduction" (239), "reproductive process" (227), and "viral reproduction" (15) (Fig. 3).…”

Disruption of FEM1C-W gene in zebra finch: evolutionary insights on avian ZW genes

“…The FEM-1, FEM-2, and FEM-3 proteins form a complex with CUL-2 that regulates the activity of the TRA-1, a DNA-binding zinc finger transcription factor that regulates the DM domain gene mab-3, which in turn regulates male sexual development (Sokol and Kuwabara 2000;Starostina et al 2007;Kuwabara 2007).…”

Genetics of germ cell development

“…[62][63][64][65][66][67][68] TRA-1 is inhibited by FEM-3, which acts along with the additional factors FEM-1 and FEM-2 to push the germ cells toward continued spermatogenesis. 69,70 FEM-3 is opposed by the RNA-binding protein DAZ-1, which promotes the switch to OOGENESIS. 71 DAZ-1 also promotes transcription of fbf-1 and fbf-2 mRNAs, and the FBF-1 and FBF-2 proteins repress fem-3 translation; as a result, the FBF proteins act both to inhibit meiosis and to promote entry into oogenesis.…”