Many biological processes, such as development and cell cycle progression are tightly controlled by selective ubiquitin-dependent degradation of key substrates. In this pathway, the E3-ligase recognizes the substrate and targets it for degradation by the 26S proteasome. The SCF (Skp1–Cul1–F-box) and ECS (Elongin C–Cul2–SOCS box) complexes are two well-defined cullin-based E3-ligases1,2,3. The cullin subunits serve a scaffolding function and interact through their C terminus with the RING-finger-containing protein Hrt1/Roc1/Rbx1, and through their N terminus with Skp1 or Elongin C, respectively. In Caenorhabditis elegans, the ubiquitin-ligase activity of the CUL-3 complex is required for degradation of the microtubule-severing protein MEI-1/katanin at the meiosis-to-mitosis transition4. However, the molecular composition of this cullin-based E3-ligase is not known. Here we identified the BTB-containing protein MEL-26 as a component required for degradation of MEI-1 in vivo. Importantly, MEL-26 specifically interacts with CUL-3 and MEI-1 in vivo and in vitro, and displays properties of a substrate-specific adaptor. Our results suggest that BTB-containing proteins may generally function as substrate-specific adaptors in Cul3-based E3-ubiquitin ligases.
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We are grateful to the C. elegans Genetics Centre (funded by the NIH National Centre for Research Resources) for providing strains. We thank R. Fischer for generation of the monoclonal anti-MEL-26 antibody, P. Gönczy for introducing L.P. to C. elegans and for sharing material and reagents, P. Weissert for help with worm liquid cultures, J. M. Bellanger and I. Sumara for suggestions, P. Wiget for help with microscopy, and P. Gönczy for critical reading of the manuscript. L.P. was supported by a Long-Term Fellowship from the Federation of European Biochemical Societies (FEBS) and a Fellowship from Roche, T.K. by a predoctoral fellowship from the American Heart Association, J.H.W. by an NIH Molecular Biology Training Grant, P.E.M. by grants from the Canadian Institutes of Health Research and the Alberta Heritage Foundation for Medical Research, B.B. by the NIH and M.P. by the ETHZ and the Swiss National Science Foundation.
The authors declare that they have no competing financial interests.
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Pintard, L., Willis, J., Willems, A. et al. The BTB protein MEL-26 is a substrate-specific adaptor of the CUL-3 ubiquitin-ligase. Nature 425, 311–316 (2003). https://doi.org/10.1038/nature01959
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