A dual role for K63-linked ubiquitin chains in multivesicular body biogenesis and cargo sorting

Erpapazoglou, Zoi; Dhaoui, Manel; Pantazopoulou, Marina; Giordano, Francesca; Mari, Muriel; Léon, Sébastien; Raposo, Graça; Reggiori, Fulvio; Haguenauer‐Tsapis, Rosine

doi:10.1091/mbc.e11-10-0891

Cited by 55 publications

(62 citation statements)

References 106 publications

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“…Furthermore, an EGFR mutant that can not be ubiquitylated fails to engage the ESCRT machinery and induce inward budding at the late endosome (Eden et al, 2012). In Saccharomyces cerevisiae cargo ubiquitylation is required for multivesicular body formation (Macdonald et al, 2012) and strains defective in K63-linked ubiquitylation show changes in the structure of multivesicular bodies (Erpapazoglou et al, 2012). Therefore, an interesting possible explanation for our observations is that RNF126 and Rabring7, through their ubiquitin-binding zinc finger domains, might associate with multiple cargo modified by another E3 and regulate their progression through the endocytic system.…”

Section: Discussionmentioning

confidence: 99%

The E3 ubiquitin ligases RNF126 and Rabring7 regulate endosomal sorting of the Epidermal Growth Factor Receptor

Smith¹,

Berry²,

McGlade³

2013

Journal of Cell Science

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SummaryActivation of the epidermal growth factor receptor (EGFR) results in internalization and ubiquitin-dependent endosomal sorting, leading to lysosomal degradation. Here we describe the role of the RING-finger-domain-containing protein RNF126 and the related protein, Rabring7 in EGFR endosomal sorting. We demonstrate that RNF126 specifies K48-linked chains with UbcH5b and also functions with Ubc13/Uev1a to form K63-linked chains in vitro. RNF126 and Rabring7 associate with the EGFR through a ubiquitin-binding zinc finger domain and both E3 ubiquitin ligases promote ubiquitylation of EGFR. In the absence of c-Cbl or in cells expressing Cbl-70Z, the binding of RNF126 and Rabring7 to the EGFR is reduced, suggesting that RNF126 and Rabring7 function downstream of c-Cbl. In HeLa cells depleted of either RNF126 or Rabring7 the EGFR is retained in a late endocytic compartment and is inefficiently degraded. In addition, depletion of RNF126 or Rabring7 destabilizes ESCRT-II and reduces the number of multivesicular bodies formed after EGF stimulation. We also show that the depletion of Rabring7 attenuates the degradation of MET and that both RNF126 and Rabring7 regulate the sorting of CXCR4 from an early endocytic compartment. Together these data suggest that RNF126 and Rabring7 play a role in the ubiquitin-dependent sorting and downregulation of membrane receptors.

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Section: Discussionmentioning

confidence: 99%

The E3 ubiquitin ligases RNF126 and Rabring7 regulate endosomal sorting of the Epidermal Growth Factor Receptor

Smith¹,

Berry²,

McGlade³

2013

Journal of Cell Science

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“…K63-linked chains do not end up in the proteasome as they bind specifically to the ESCRT-0 complex, specifically to UIMs found in HRS and STAM1 components [27,89]. These interactions condense proteins modified with K63-linked poly-ubiquitin chains into endosomes, promoting their import into ILVs of MVBs and possibly, their subsequent delivery into exosomes [90]. In fact, K63-linked chain is the most representative ubiquitin topology found in EVs [84] (Fig.…”

Section: Deciphering the Ubiquitin Code In Evsmentioning

confidence: 99%

Post-translational add-ons mark the path in exosomal protein sorting

Moreno-Gonzalo

Fernández-Delgado

Sánchez‐Madrid

2017

Cell. Mol. Life Sci.

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“…ILV formation and cargo sorting are mediated by the endosomal sorting complex required for transport (ESCRT) machinery (Raiborg and Stenmark, 2009). Previous studies indicate that K63-linked polyubiquitylation of cargo proteins specifically functions as an ESCRT-dependent sorting signal to ILVs rather than as an internalization signal (Huang et al, 2006;Barriere et al, 2007;Lauwers et al, 2010;Erpapazoglou et al, 2012), although other reports suggest that multiple or even single monoubiquitylation is sufficient for MVB sorting (Stringer and Piper, 2011). Thus, the exact role of K63-linked ubiquitylation in endocytic processes remains controversial.…”

Section: Introductionmentioning

confidence: 99%

Fertilization-induced K63-linked ubiquitylation mediates clearance of maternal membrane proteins

et al. 2014

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In Caenorhabditis elegans, fertilization triggers endocytosis and rapid turnover of maternal surface membrane proteins in lysosomes, although the precise mechanism of this inducible endocytosis is unknown. We found that high levels of K63-linked ubiquitin chains transiently accumulated on endosomes upon fertilization. Endocytosis and the endosomal accumulation of ubiquitin were both regulated downstream of the anaphase-promoting complex, which drives the oocyte's meiotic cell cycle after fertilization. The clearance of maternal membrane proteins and the accumulation of K63-linked ubiquitin on endosomes depended on UBC-13 and UEV-1, which function as an E2 complex that specifically mediates chain elongation of K63-linked polyubiquitin. CAV-1-GFP, an endocytic cargo protein, was modified with K63-linked polyubiquitin in a UBC-13/UEV-1-dependent manner. In ubc-13 or uev-1 mutants, CAV-1-GFP and other membrane proteins were internalized from the plasma membrane normally after fertilization. However, they were not efficiently targeted to the multivesicular body (MVB) pathway but recycled to the cell surface. Our results suggest that UBC-13-dependent K63-linked ubiquitylation is required for proper MVB sorting rather than for internalization. These results also demonstrate a developmentally controlled function of K63-linked ubiquitylation.

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A dual role for K63-linked ubiquitin chains in multivesicular body biogenesis and cargo sorting

Cited by 55 publications

References 106 publications

The E3 ubiquitin ligases RNF126 and Rabring7 regulate endosomal sorting of the Epidermal Growth Factor Receptor

The E3 ubiquitin ligases RNF126 and Rabring7 regulate endosomal sorting of the Epidermal Growth Factor Receptor

Post-translational add-ons mark the path in exosomal protein sorting

Fertilization-induced K63-linked ubiquitylation mediates clearance of maternal membrane proteins

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