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Vol. 17, Issue 6, 2489-2497, June 2006

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CNF1-induced Ubiquitylation and Proteasome Destruction of Activated RhoA Is Impaired in Smurf1^–/– Cells

Laurent Boyer^*, Laurent Turchi, Benoit Desnues, Anne Doye^*, Gilles Ponzio, Jean-Louis Mege, Motozo Yamashita, Ying E. Zhang, Jacques Bertoglio^||, Gilles Flatau^*, Patrice Boquet^*, and Emmanuel Lemichez^*

*Faculté de Médecine, Institut National de la Santé et de la Recherche Médicale, U627, 06107 Nice Cedex 2, France; Faculté de Médecine, Institut National de la Santé et de la Recherche Médicale, U634, 06107 Nice Cedex 2, France; Université de la Méditerranée, Unité des Rickettsies, Centre National de la Recherche Scientifique, Unité Mixte de Recherche, 6020, Faculté de Médecine, 13385 Marseille, France; Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892; and ^||Faculté de Pharmacie, Institut National de la Santé et de la Recherche Médicale, U461, Paris-XI, 92290 Chatenay-Malabry, France

Submitted September 20, 2005; Revised February 24, 2006; Accepted March 6, 2006
Monitoring Editor: Ralph Isberg

Ubiquitylation of RhoA has emerged as an important aspect of both the virulence of Escherichia coli producing cytotoxic necrotizing factor (CNF) 1 toxin and the establishment of the polarity of eukaryotic cells. Owing to the molecular activity of CNF1, we have investigated the relationship between permanent activation of RhoA catalyzed by CNF1 and subsequent ubiquitylation of RhoA by Smurf1. Using Smurf1-deficient cells and by RNA interference (RNAi)-mediated Smurf1 knockdown, we demonstrate that Smurf1 is a rate-limiting and specific factor of the ubiquitin-mediated proteasomal degradation of activated RhoA. We further show that the cancer cell lines HEp-2, human embryonic kidney 293 and Vero are specifically deficient in ubiquitylation of either activated Rac, Cdc42, or Rho, respectively. In contrast, CNF1 produced the cellular depletion of all three isoforms of Rho proteins in the primary human cell types we have tested. We demonstrate that ectopic expression of Smurf1 in Vero cells, deficient for RhoA ubiquitylation, restores ubiquitylation of the activated forms of RhoA. We conclude here that Smurf1 ubiquitylates activated RhoA and that, in contrast to human primary cell types, some cancer cell lines have a lower ubiquitylation capacity of specific Rho proteins. Thus, both CNF1 and transforming growth factor- trigger activated RhoA ubiquitylation through Smurf1 ubiquitin-ligase.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E05-09-0876) on March 15, 2006.

Address correspondence to: Emmanuel Lemichez ( lemichez{at}unice.fr)

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