ReviewUbiquitin ligase adaptors: Regulators of ubiquitylation and endocytosis of plasma membrane proteins
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
References (91)
- et al.
Endocytosis conducts the cell signaling orchestra
Cell
(2006) - et al.
Role of ubiquitin- and Ubl-binding proteins in cell signaling
Curr. Opin. Cell Biol.
(2007) - et al.
Ubiquitin and endocytic internalization in yeast and animal cells
Biochim. Biophys. Acta
(2004) - et al.
Ubiquitin in trafficking: The network at work
Exp. Cell. Res.
(2009) - et al.
Ubiquitination of a yeast plasma membrane receptor signals its ligand-stimulated endocytosis
Cell
(1996) - et al.
The C2 domain of the ubiquitin protein ligase Nedd4 mediates Ca2+-dependent plasma membrane localization
J. Biol. Chem.
(1997) - et al.
Ubiquitination mediated by the Npi1p/Rsp5p ubiquitin-protein ligase is required for endocytosis of the yeast uracil permease
J. Biol. Chem.
(1996) - et al.
Negative control of heavy metal uptake by the Saccharomyces cerevisiae BSD2 gene
J. Biol. Chem.
(1997) - et al.
Ubiquitin is required for sorting to the vacuole of the yeast general amino acid permease, Gap1
J. Biol. Chem.
(2001) - et al.
Arrestin-related ubiquitin-ligase adaptors regulate endocytosis and turnover of proteins at the cell surface
Cell
(2008)