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Molecular and Cellular Biology, June 2007, p. 4526-4540, Vol. 27, No. 12
0270-7306/07/$08.00+0     doi:10.1128/MCB.01724-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

CIF-1, a Shared Subunit of the COP9/Signalosome and Eukaryotic Initiation Factor 3 Complexes, Regulates MEL-26 Levels in the Caenorhabditis elegans Embryo

Sarah Luke-Glaser,¹ Marcia Roy,² Brett Larsen,² Thierry Le Bihan,³ Pavel Metalnikov,² Mike Tyers,^2, Matthias Peter,^1, and Lionel Pintard^2,4*,

Swiss Federal Institute of Technology Zurich (ETH), Institute of Biochemistry, HPM G8, ETH Hoenggerberg, 8093 Zurich, Switzerland,¹ Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada,² The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Ontario M5G 2M9, Canada,³ Institut Jacques Monod-CNRS, Université Paris VI et VII, 2 Place Jussieu Tour 43, 75251 Paris Cedex 05, France⁴

Received 12 September 2006/ Returned for modification 16 November 2006/ Accepted 7 March 2007

The COP9/signalosome (CSN) is an evolutionarily conserved macromolecular complex that regulates the cullin-RING ligase (CRL) class of E3 ubiquitin ligases, primarily by removing the ubiquitin-like protein Nedd8 from the cullin subunit. In the Caenorhabditis elegans embryo, the CSN controls the degradation of the microtubule-severing protein MEI-1 through CUL-3 deneddylation. However, the molecular mechanisms of CSN function and its subunit composition remain to be elucidated. Here, using a proteomic approach, we have characterized the CSN and CUL-3 complexes from C. elegans embryos. We show that the CSN physically interacts with the CUL-3-based CRL and regulates its activity by counteracting the autocatalytic instability of the substrate-specific adaptor MEL-26. Importantly, we identified the uncharacterized protein K08F11.3/CIF-1 (for CSN-eukaryotic initiation factor 3 [eIF3]) as a stoichiometric and functionally important subunit of the CSN complex. CIF-1 appears to be the only ortholog of Csn7 encoded by the C. elegans genome, but it also exhibits extensive sequence similarity to eIF3m family members, which are required for the initiation of protein translation. Indeed, CIF-1 binds eIF-3.F and inactivation of cif-1 impairs translation in vivo. Taken together, our results indicate that CIF-1 is a shared subunit of the CSN and eIF3 complexes and may therefore link protein translation and degradation.

Published ahead of print on 2 April 2007.

Mike Tyers, Matthias Peter, and Lionel Pintard contributed equally to this study.