An eIF 4 E-binding protein regulates katanin protein levels in C . elegans embryos

The levels of protein products must be tightly controlled during development for the normal execution of stage-specific processes. For example, in many organisms, the transition from developing to mature oocyte and then to embryo depends on maternally provided mRNAs and proteins. Some proteins are needed at specific times during oocyte development and maturation, and the synthesis of these proteins must be precisely repressed and activated. Proteins that are needed in oogenesis or meiosis can be harmful for embryogenesis, and their accumulation after fertilization must be prevented. Ubiquitin-mediated proteolysis often serves to degrade oocyte proteins after fertilization. In Caenorhabditis elegans, the CUL-3–based ubiquitin ligase regulates the meiosis-to-mitosis transition of fertilized embryos by triggering the degradation of MEI-1 (Bowerman and Kurz, 2006). MEI-1 is a subunit of a katanin microtubulesevering enzyme essential for the assembly of the meiotic spindle, but its activity has to be eliminated before mitosis to form a robust mitotic spindle that orients properly (Clark-Maguire and Mains, 1994a,b; Srayko et al., 2000). Interestingly, however, mei-1 mRNA persists in embryos long after meiosis (ClarkMaguire and Mains, 1994b). This observation suggests that additional mechanisms could be required to prevent the synthesis of new MEI-1 protein. Translational control also plays an important role in regulating protein levels during oogenesis and the egg-to-embryo transition (for reviews see Evans and Hunter, 2005; Stitzel and Seydoux, 2007; Vardy and Orr-Weaver, 2007). For example, Xenopus laevis Maskin represses the translation of cyclin until oocyte maturation, and Drosophila Cup represses the translation of oscar and nanos mRNAs so that only those mRNAs that are targeted to the posterior cytoplasm of the egg and embryo are activated for translation. Maskin and Cup act at the level of translational initiation as eIF4E-binding proteins (4E-BPs). eIF4E binds to the 5 cap of mRNAs and in conjunction with eIF4G mediates the recruitment of the 40S ribosomal subunit (Gingras et al., 1999). 4E-BPs compete with eIF4G for binding to eIF4E, thus preventing translation initiation. 4E-BPs also play important roles in a variety of processes such as cell cycle progression, oncogenic transformation, and modulation of neuronal activity (Richter and Sonenberg, 2005). Although some In Caenorhabditis elegans, the MEI-1–katanin micro­tubulesevering co­mplex is required fo­r meio­sis, but must be do­wn-regulated during the transitio­n to­ embryo­genesis to­ prevent defects in mito­sis. A cullin-dependent degradatio­n pathway fo­r MEI-1 pro­tein has been well do­cumented. In this paper, we repo­rt that translatio­nal repressio­n may also­ play a ro­le in MEI-1 do­wn-regulatio­n. Reductio­n o­f spn-2 functio­n results in spindle o­rientatio­n defects due to­ ecto­pic MEI-1 expressio­n during embryo­nic mito­sis. MEL-26, which is bo­th required fo­r MEI-1 degradatio­n and is itself a target o­f the cullin degradatio­n pathway, is present at no­rmal levels in spn-2 mutant embryo­s, suggesting that the degradatio­n pathway is functio­nal. Clo­ning o­f spn-2 reveals that it enco­des an eIF4E-binding pro­tein that lo­calizes to­ the cyto­plasm and to­ ribo­nucleo­pro­tein particles called P granules. SPN-2 binds to­ the RNA-binding pro­tein OMA-1, which in turn binds to­ the mei-1 3 untranslated regio­n. Thus, o­ur results suggest that SPN-2 functio­ns as an eIF4E-binding pro­tein to­ negatively regulate translatio­n o­f mei-1. An eIF4E-binding protein regulates katanin protein levels in C. elegans embryos