Multiple mechanisms inactivate the LIN-41 RNA-binding protein to ensure a robust oocyte-to-embryo transition in caenorhabditis elegans

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Abstract

In the nematode Caenorhabditis elegans, the conserved LIN-41 RNA-binding protein is a translational repressor that coordinately controls oocyte growth and meiotic maturation. LIN-41 exerts these effects, at least in part, by preventing the premature activation of the cyclin-dependent kinase CDK-1. Here we investigate the mechanism by which LIN-41 is rapidly eliminated upon the onset of meiotic maturation. Elimination of LIN-41 requires the activities of CDK-1 and multiple SCF (Skp1, Cul1, and F-box protein)-type E3 ubiquitin ligase subunits, including the conserved substrate adaptor protein SEL-10/Fbw7/Cdc4, suggesting that LIN-41 is a target of ubiquitin-mediated protein degradation. Within the LIN-41 protein, two nonoverlapping regions, Deg-A and Deg-B, are individually necessary for LIN-41 degradation; both contain several potential phosphodegron sequences, and at least one of these sequences is required for LIN-41 degradation. Finally, Deg-A and Deg-B are sufficient, in combination, to mediate SEL-10-dependent degradation when transplanted into a different oocyte protein. Although LIN-41 is a potent inhibitor of protein translation and M phase entry, the failure to eliminate LIN-41 from early embryos does not result in the continued translational repression of LIN-41 oocyte messenger RNA targets. Based on these observations, we propose a model for the elimination of LIN-41 by the SEL-10 E3 ubiquitin ligase and suggest that LIN-41 is inactivated before it is degraded. Furthermore, we provide evidence that another RNA-binding protein, the GLD-1 tumor suppressor, is regulated similarly. Redundant mechanisms to extinguish translational repression by RNA-binding proteins may both control and provide robustness to irreversible developmental transitions, including meiotic maturation and the oocyte-to-embryo transition.

Original languageEnglish (US)
Pages (from-to)1011-1037
Number of pages27
JournalGenetics
Volume210
Issue number3
DOIs
StatePublished - Nov 2018

Bibliographical note

Funding Information:
We are grateful to Swathi Arur, Sarah Crittenden, Claire de la Cova, Daniel Dickinson, Bob Goldstein, Barth Grant, Iva Greenwald, Judith Kimble, Tim Schedl, and Dustin Updike for providing strains or reagents. We thank G. W. Gant Luxton for the use of his spinning disc confocal microscope. We also thank WormBase for sequences and annotations. We thank Cynthia Kenyon for discussions on GLD-1 regulation. Ann Rougvie and Todd Starich provided helpful suggestions during the course of this work. Some strains were provided by the Caenorhabditis Genetics Center, which is funded by grant P40OD010440 from the National Institutes of Health Office of Research Infrastructure Programs. This work was supported by National Institutes of Health grant GM57173 (to D.G.).

Keywords

  • Oocyte meiotic maturation
  • Oocyte-to-embryo transition
  • RNA-binding proteins
  • Translational regulation
  • Ubiquitin-mediated protein degradation

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