Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2006 May 22;173(4):463-8.
doi: 10.1083/jcb.200602082. Epub 2006 May 15.

Riding the DUBway: regulation of protein trafficking by deubiquitylating enzymes

Susan M Millard  1 , Stephen A Wood
Affiliations
Review

Riding the DUBway: regulation of protein trafficking by deubiquitylating enzymes

Susan M Millard et al. J Cell Biol. .

Abstract

Ubiquitylation is a key regulator of protein trafficking, and much about the functions of ubiquitin ligases, which add ubiquitin to substrates in this regulation, has recently come to light. However, a clear understanding of ubiquitin-dependent protein localization cannot be achieved without knowledge of the role of deubiquitylating enzymes (DUBs). DUBs, by definition, function downstream in ubiquitin pathways and, as such, have the potential to be the final editors of protein ubiquitylation status, thus determining substrate fate. This paper assimilates the current evidence concerning the substrates and activities of DUBs that regulate protein trafficking.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
DUBs influence membrane protein trafficking at a variety of trafficking locations. Conjugation of ubiquitin (red circles) is involved in the trafficking of various cargo, including receptor tyrosine kinases (green) and G protein–coupled receptors (black curved lines). (A) The DUB USP4 regulates ubiquitin–proteasome-mediated degradation of misfolded forms of a Gs-coupled receptor at the ER. (B) The yeast DUB Ubp3 functionally regulates proteins that are necessary for vesicular transport from the ER to Golgi and also Golgi to ER retrograde transport. (C) At the plasma membrane, ubiquitylation, which often occurs in response to receptors binding ligand (triangles), acts as an internalization signal and as a regulatory modification on the protein-trafficking machinery. Epsin, a component of the clathrin-mediated endocytosis machinery, is regulated by FAM/USP9X. (D) After internalization protein cargo is trafficked through multiple endosomes, it is eventually recycled to the plasma membrane or degraded at the lysosome. Recycling to the plasma membrane occurs if the cargo is deubiquitylated (represented by a black dashed line) before ubiquitin signals the sorting of the cargo into internal vesicles. Sorting cargo into internal vesicles destines it for lysosomal degradation. Deubiquitylation of the cargo during sorting is necessary for ubiquitin recycling. Two DUB–cargo interactions that antagonize receptor down-regulation have been proposed: AMSH and EGFR or UCH37 and type I TGF-β receptor. In contrast, USP8 appears to facilitate the down-regulation of EGFR. DUBs also regulate the endosomal trafficking machinery indirectly. The overexpression of Ubp1 in yeast results in impaired lysosomal trafficking of at least two cargo proteins but does not alter their ubiquitylation status.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Alwan, H.A., E.J. van Zoelen, and J.E. van Leeuwen. 2003. Ligand-induced lysosomal epidermal growth factor receptor (EGFR) degradation is preceded by proteasome-dependent EGFR de-ubiquitination. J. Biol. Chem. 278:35781–35790. - PubMed
    1. Amerik, A.Y., and M. Hochstrasser. 2004. Mechanism and function of deubiquitinating enzymes. Biochim. Biophys. Acta. 1695:189–207. - PubMed
    1. Amerik, A.Y., J. Nowak, S. Swaminathan, and M. Hochstrasser. 2000. The Doa4 deubiquitinating enzyme is functionally linked to the vacuolar protein-sorting and endocytic pathways. Mol. Biol. Cell. 11:3365–3380. - PMC - PubMed
    1. Bilodeau, P.S., S.C. Winistorfer, W.R. Kearney, A.D. Robertson, and R.C. Piper. 2003. Vps27-Hse1 and ESCRT-I complexes cooperate to increase efficiency of sorting ubiquitinated proteins at the endosome. J. Cell. Biol. 163:237–243. - PMC - PubMed
    1. Bowers, K., S.C. Piper, M.A. Edeling, S.R. Gray, D.J. Owen, P.J. Lehner, and J.P. Luzio. 2006. Degradation of endocytosed epidermal growth factor and virally ubiquitinated major histocompatibility complex class I is independent of mammalian ESCRTII. J. Biol. Chem. 281:5094–5105. - PubMed

Publication types

MeSH terms