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| Subject Categories: Membranes & Transport |
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| The EMBO Journal
(2006) 25, 932–942, doi:10.1038/sj.emboj.7600989 Published online 16 February 2006 |
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| Ubiquitylation of leptin receptor OB-Ra regulates its clathrin-mediated endocytosis |
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| Sandrine Belouzard and Yves Rouillé |
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Centre National de la Recherche Scientifique, Unité Propre de Recherche 2511, Institut Pasteur de Lille, Lille Cedex, France To whom correspondence should be addressed Yves Rouillé, Centre National de la Recherche Scientifique, Unité Propre de Recherche 2511, Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 447, 59021 Lille Cedex, France. E-mail: yves.rouille@ibl.fr Received 26 July 2005; Accepted 17 January 2006; Published online 16 February 2006. |
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| Abstract |
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| Leptin receptors are constitutively endocytosed in a ligand-independent manner. To study their endocytosis, leptin receptors OB-Ra and OB-Rb were expressed in HeLa cells. Both receptor isoforms were ubiquitylated, internalized by clathrin-mediated endocytosis and transported to Hrs-positive endosomes after their internalization. Proteasome inhibitors inhibited OB-Ra but not OB-Rb internalization from the cell surface. OB-Ra ubiquitylation occurred on lysine residues K877 and K889 in the cytoplasmic tail, the mutation of which abolished OB-Ra internalization. Fusion of an ubiquitin molecule at the C-terminus of an OB-Ra construct defective both in ubiquitylation and endocytosis restored clathrin-dependent endocytosis of the receptor. The internalization of this constitutively mono-ubiquitylated construct was no longer sensitive to proteasome inhibitors, which inhibited OB-Ra endocytosis by blocking its ubiquitylation. Fusion of an ubiquitin molecule to a transferrin receptor deleted from its own endocytosis motif restored clathrin-mediated endocytosis. We propose that mono-ubiquitin conjugates act as internalization motifs for clathrin-dependent endocytosis of leptin receptor OB-Ra. |
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| Keywords: endocytosis motif, leptin receptor, proteasome, siRNA, ubiquitin |
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