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The F-box protein Slimb controls the levels of clock proteins Period and Timeless

Nature volume 420, pages 178–182 (2002)Cite this article

Abstract

The Drosophila circadian clock is driven by daily fluctuations of the proteins Period and Timeless, which associate in a complex and negatively regulate the transcription of their own genes1,2. Protein phosphorylation has a central role in this feedback loop, by controlling Per stability in both cytoplasmic and nuclear compartments3,4,5,6 as well as Per/Tim nuclear transfer7,8. However, the pathways regulating degradation of phosphorylated Per and Tim are unknown. Here we show that the product of the slimb (slmb) gene9—a member of the F-box/WD40 protein family of the ubiquitin ligase SCF complex that targets phosphorylated proteins for degradation10,11,12,13—is an essential component of the Drosophila circadian clock. slmb mutants are behaviourally arrhythmic, and can be rescued by targeted expression of Slmb in the clock neurons. In constant darkness, highly phosphorylated forms of the Per and Tim proteins are constitutively present in the mutants, indicating that the control of their cyclic degradation is impaired. Because levels of Per and Tim oscillate in slmb mutants maintained in light:dark conditions, light- and clock-controlled degradation of Per and Tim do not rely on the same mechanisms.

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Figure 1: Locomotor activity in LD cycles.
Figure 2: Per and Tim proteins and RNAs in slmbm mutants.
Figure 3: Slmb protein expression and interactions.

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Acknowledgements

We thank M. Boudinot for the Faas software, M. Serrier and L. Collet for help with the figures, M. Rosbash, P. Emery, A. Klarsfeld, J.-F. Julien and E. Petrochilo for their comments and suggestions on the manuscript, as well as J. Champagnat and J.-D. Vincent for their continuous support. We thank I. Miletich for the unpublished UAS-slmb line, and R. Myers, L. Saez, R. Stanewsky and D. Virshup for providing antibodies or constructs. This work was supported by CNRS (ATIPE “Développement” and appel d'offres “Biologie cellulaire”) and Fondation pour la Recherche Médicale. F.R. is supported by INSERM.

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  1. Institut de Neurobiologie Alfred Fessard (NGI, CNRS UPR 2216) and Centre de Génétique Moléculaire (CNRS UPR 2167), Centre National de la Recherche Scientifique, av. de la terrasse, 91198, Gif-sur-Yvette, France

    Bernadette Limbourg-Bouchon & François Rouyer

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  1. Brigitte Grima
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Correspondence to François Rouyer.

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Grima, B., Lamouroux, A., Chélot, E. et al. The F-box protein Slimb controls the levels of clock proteins Period and Timeless. Nature 420, 178–182 (2002). https://doi.org/10.1038/nature01122

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