Mammalian class E vps proteins recognize ubiquitin and act in the removal of endosomal protein–ubiquitin conjugates

Bishop, Naomi; Horman, Alistair; Woodman, Philip

doi:10.1083/jcb.200112080

Cited by 251 publications

(325 citation statements)

References 34 publications

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“…To investigate this possibility, we overexpressed GFP-tagged HRS (also known as HGS), which is a component of the ESCRT-0 complex that initiates recruitment of the ESCRT machinery in early endosomes (Williams and Urbé, 2007). Overexpression of HRS negatively perturbs the ESCRT pathway, promoting accumulation of ESCRT-I in early endosomes that become enlarged (Bache et al, 2003;Bishop et al, 2002). Overexpression of cytosolic GFP did not seem to alter the distribution of γ2 and CD4 downregulated by Nef (Fig.…”

Section: Knockdown Of γ2 Alleviates Surface Depletion Of Cd4 By Nefmentioning

confidence: 86%

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CD4 downregulation by the HIV-1 protein Nef reveals distinct roles for the γ1 and γ2 subunits of the AP-1 complex in protein trafficking

Tavares

Silva

Silva-Januário

et al. 2017

Journal of Cell Science

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The HIV accessory protein Nef is a major determinant of viral pathogenesis that facilitates viral particle release, prevents viral antigen presentation and increases infectivity of new virus particles. These functions of Nef involve its ability to remove specific host proteins from the surface of infected cells, including the CD4 receptor. Nef binds to the adaptor protein 2 (AP-2) and CD4 in clathrin-coated pits, forcing CD4 internalization and its subsequent targeting to lysosomes. Herein, we report that this lysosomal targeting requires a variant of AP-1 containing isoform 2 of γ-adaptin (AP1G2, hereafter γ2). Depletion of the γ2 or μ1A (AP1M1) subunits of AP-1, but not of γ1 (AP1G1), precludes Nef-mediated lysosomal degradation of CD4. In γ2-depleted cells, CD4 internalized by Nef accumulates in early endosomes and this alleviates CD4 removal from the cell surface. Depletion of γ2 also hinders EGFR-EGF-complex targeting to lysosomes, an effect that is not observed upon γ1 depletion. Taken together, our data provide evidence that the presence of γ1 or γ2 subunits delineates two distinct variants of AP-1 complexes, with different functions in protein sorting.

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Section: Knockdown Of γ2 Alleviates Surface Depletion Of Cd4 By Nefmentioning

confidence: 86%

“…3). Moreover, upon artificially stabilizing ESCRT-I in early endosomes by overexpression of HRS (Bache et al, 2003;Bishop et al, 2002), internalized CD4 accumulates in enlarged HRS-GFP-positive endosomes, where colocalization with γ2 is prominent (Fig. 7).…”

Section: Discussionmentioning

confidence: 97%

CD4 downregulation by the HIV-1 protein Nef reveals distinct roles for the γ1 and γ2 subunits of the AP-1 complex in protein trafficking

Tavares

Silva

Silva-Januário

et al. 2017

Journal of Cell Science

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“…First, overexpression of Hrs causes the enlargement of early endosomes (Komada et al, 1997). Cell surface receptors such as EGFR and transferrin receptor, as well as other ubiquitinated proteins, are accumulated on these endosomes (Komada et al, 1997;Bishop et al, 2002;Raiborg et al, 2002;Morino et al, 2004). UBPY colocalized with overexpressed Hrs on the aberrant endosomes ( Figure 5).…”

Section: Subcellular Site Of Ubpy-mediated Egfr Deubiquitinationmentioning

confidence: 99%

Regulation of Epidermal Growth Factor Receptor Down-Regulation by UBPY-mediated Deubiquitination at Endosomes

Mizuno

Iura

Mukai

et al. 2005

MBoC

259

264

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Ligand-activated receptor tyrosine kinases undergo endocytosis and are transported via endosomes to lysosomes for degradation. This "receptor down-regulation" process is crucial to terminate the cell proliferation signals produced by activated receptors. During the process, ubiquitination of the receptors serves as a sorting signal for their trafficking from endosomes to lysosomes. Here, we describe the role of a deubiquitinating enzyme UBPY/USP8 in the down-regulation of epidermal growth factor (EGF) receptor (EGFR). Overexpression of UBPY reduced the ubiquitination level of EGFR and delayed its degradation in EGF-stimulated cells. Immunopurified UBPY deubiquitinated EGFR in vitro. In EGF-stimulated cells, UBPY underwent ubiquitination and bound to EGFR. Overexpression of Hrs or a dominant-negative mutant of SKD1, proteins that play roles in the endosomal sorting of ubiquitinated receptors, caused the accumulation of endogenous UBPY on exaggerated endosomes. A catalytically inactive UBPY mutant clearly localized on endosomes, where it overlapped with EGFR when cells were stimulated with EGF. Finally, depletion of endogenous UBPY by RNA interference resulted in elevated ubiquitination and accelerated degradation of EGF-activated EGFR. We conclude that UBPY negatively regulates the rate of EGFR down-regulation by deubiquitinating EGFR on endosomes.

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“…Receptors labeled with single ubiquitin (Ub) molecules are recognized in early endosomes by Hrs/Vps27p and ESCRT I complexes which sort receptors toward late endosomes (10). At the limiting membrane of targeted vesicles, components of the ESCRT II/III complex (11,12) segregate ubiquitinylated molecules into IMBs (13,14). In some cases ubiquitinylation of receptors, or of components of the endocytic machinery, can initiate sorting into clathrin-coated pits and receptor endocytosis (15,16).…”

mentioning

confidence: 99%

Ubiquitinylation of Igβ Dictates the Endocytic Fate of the B Cell Antigen Receptor

Zhang

Veselits

O'Neill

et al. 2007

The Journal of Immunology

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In both infection and autoimmunity, the development of high-affinity Abs and memory requires B cells to efficiently capture and process Ags for presentation to cognate T cells. Although a great deal is known about how Ags are processed, the molecular mechanisms by which the BCR captures Ag for processing are still obscure. In this study, we demonstrate that the Igβ component of the BCR is diubiquitinylated and that this is dependent on the E3 ligase Itch. Itch−/− B lymphocytes manifest both a defect in ligand-induced BCR internalization and endocytic trafficking to late endosomal Ag-processing compartments. In contrast, analysis of ubiquitinylation-defective receptors demonstrated that the attachment of ubiquitins to Igβ is required for endosomal sorting and for the presentation of Ag to T cells, yet, ubiquitinylation is dispensable for receptor internalization. Membrane-bound Igμ was not detectably ubiquitinylated nor were the conserved lysines in the mu cytosolic tail required for trafficking to late endosomes. These results demonstrate that ubiquitinylation of a singular substrate, Igβ, is required for a specific receptor trafficking event. However, they also reveal that E3 ligases play a broader role in multiple processes that determine the fate of Ag-engaged BCR complexes.

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Mammalian class E vps proteins recognize ubiquitin and act in the removal of endosomal protein–ubiquitin conjugates

Cited by 251 publications

References 34 publications

CD4 downregulation by the HIV-1 protein Nef reveals distinct roles for the γ1 and γ2 subunits of the AP-1 complex in protein trafficking

CD4 downregulation by the HIV-1 protein Nef reveals distinct roles for the γ1 and γ2 subunits of the AP-1 complex in protein trafficking

Regulation of Epidermal Growth Factor Receptor Down-Regulation by UBPY-mediated Deubiquitination at Endosomes

Ubiquitinylation of Igβ Dictates the Endocytic Fate of the B Cell Antigen Receptor

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