Elsevier

Experimental Cell Research

Volume 315, Issue 9, 15 May 2009, Pages 1574-1583
Experimental Cell Research

Review
Ubiquitin ligase adaptors: Regulators of ubiquitylation and endocytosis of plasma membrane proteins

https://doi.org/10.1016/j.yexcr.2008.11.014Get rights and content

Abstract

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.

Section snippets

Role of ubiquitin ligase adaptors in the regulation of the E3/substrate interaction

Initial evidence for the role of ubiquitin in endocytosis came from independent studies performed in yeast and mammalian cells, in which internalization of various plasma membrane proteins appeared to be related to their ubiquitylation status [10], [11], [12], [13]. For example, in endocytosis mutants, endocytic substrates accumulated in their ubiquitylated form at the plasma membrane [10]. However, differences were found in the molecular mechanisms underlying this regulation, for instance

Role of adaptor proteins in the regulation of E3 catalytic activity

Recent advances in the study of transforming growth factor (TGF)-β signaling led to the identification of another Nedd4 family E3 ligase, Smurf2, in the regulation of the TGF-β type I receptor endocytosis (TGF-βRI, Ser/Thr kinase receptor). The PY-motif containing protein Smad7 binds to Smurf2 through its WW domains [69], and the Smurf2/Smad7 interaction is regulated by TGF-β signaling. Both proteins are mostly found in the nucleus at steady state, and Smad7 regulates the activity of Smurf2 at

Role of adaptor proteins in the regulation of E3 localization

The above examples indicate that the use of adaptor proteins allows a regulated recruitment of E3s to their endocytic substrates (Fig. 1D, 1), and contributes to their substrate specificity. E3 adaptors have also been reported to affect the localization of their cognate ligase, which provides another mean to regulate cargo ubiquitylation.

In particular, PY-motif containing proteins were reported to play a role in the localization of several Nedd4-related E3s. Ndfip2, which is involved in

Adaptor regulation by post-translational modifications: regulating the regulator

There is an increasing body of evidence that the steady-state level of adaptors is crucial for the proper regulation of E3 activity. Many adaptors are themselves ubiquitylated by the ligase they are regulating (Fig. 1E, 1) (see above examples, as well as N4BP1, N4BP2, Ndfip1, Ndfip2: [3,[41], [42], [43]), while others are not (for instance, N4BP3 and Grb10: Ref. [41,53]). The reasons for this are unclear, and ubiquitylation of the adaptor does not correlate with the presence/absence of PY

Conclusion

Altogether, these examples indicate that E3 adaptors are not only responsible for the recruitment of specific substrates in a given condition, but are also essential for the subcellular localization, availability, activity, and stability of the corresponding ubiquitin ligase. This adds many levels of regulation to the step at which the cargo becomes ubiquitylated and committed to being endocytosed and degraded. The surprising conservation of this mode of regulation, that exists regardless of

Acknowledgments

The authors would like to thank Sharad Kumar (IMVS, Adelaide, Australia) for sharing unpublished data, and members of our laboratory for critical reading of the manuscript. Work in our laboratory was supported by the Centre National de la Recherche Scientifique (CNRS), Universities of Paris 6 and 7, and by the Association pour la Recherche sur le Cancer (grant 3298), the CNRS ACI: BCMS, and the European Union 6th Framework Programme (Role of Ubiquitin and Ubiquitin-like Modifiers in Cellular

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