Review Ubiquitin ligase adaptors: Regulators of ubiquitylation and endocytosis of plasma membrane proteins Sébastien Léon ⁎ , Rosine Haguenauer-Tsapis ⁎ Institut Jacques Monod, UMR 7592 (Centre National de la Recherche Scientifique, Universités Paris 6 et 7), Paris, France ARTICLE INFORMATION ABSTRACT Article Chronology: Received 9 September 2008 Revised version received 21 November 2008 Accepted 23 November 2008 Available online 3 December 2008 The subcellular localization of plasma membrane proteins, such as receptors and transporters, must be finely tuned so that they can be readily downregulated in response to environmental cues. Some of these membrane proteins are post-translationally modified by conjugation to ubiquitin, which is used as a molecular tag to commit them to the endocytic pathway and promote their subsequent delivery to the lysosomes for degradation. This ubiquitylation step, which is performed by so-called ubiquitin ligases (or E3), appears therefore as a critical event for endocytosis and is subject to many levels of regulation. In this review, we focus on the regulation of cargo ubiquitylation by accessory proteins, or “adaptors”, and discuss the various ways by which they promote the action of ubiquitin ligases toward their specific cargoes. Common features emerge on this mode of regulation, which is present from yeast to human, regardless of the type of ubiquitin ligase in charge of the ubiquitylation. Finally, because these adaptors represent an additional layer of specificity in the ubiquitylation cascade, and can themselves be subject to a complex regulation, they are essential actors in the fine-tuning of endocytosis. © 2008 Elsevier Inc. All rights reserved. Keywords: Ubiquitin Substrate specificity Ubiquitin ligase Adaptor Endocytosis Nedd4 Rsp5 Cbl Arrestin Contents Role of ubiquitin ligase adaptors in the regulation of the E3/substrate interaction........................ 1575 Direct binding of substrates to ubiquitin ligases: the Nedd4 family and ion channels regulation .............. 1576 Adaptor-mediated interaction of Rsp5 with substrates in yeast ....... ......................... 1577 Adaptor-mediated recognition of endocytic substrates by Nedd4 E3s in mammals...................... 1577 Direct binding and adaptor-mediated recognition of substrates by RING E3s in mammals .................. 1578 Role of adaptor proteins in the regulation of E3 catalytic activity ....... ......................... 1578 Role of adaptor proteins in the regulation of E3 localization .......... ......................... 1579 Adaptor regulation by post-translational modifications: regulating the regulator ........................ 1579 Conclusion.................................... ......................... 1580 EXPERIMENTAL CELL RESEARCH 315 (2009) 1574 – 1583 ⁎ Corresponding authors. Institut Jacques Monod, Tour 43, aile 43-44, 2 place Jussieu, F-75251 Paris cedex 05, France. Fax: +33 1 44 27 59 94. E-mail addresses: leon@ijm.jussieu.fr (S. Léon), haguenauer@ijm.jussieu.fr (R. Haguenauer-Tsapis). 0014-4827/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.yexcr.2008.11.014 available at www.sciencedirect.com www.elsevier.com/locate/yexcr