The E3 Ubiquitin Ligase UBE3C Enhances Proteasome Processivity by Ubiquitinating Partially Proteolyzed Substrates

Chu, Bernard; Kovary, Kyle M.; Guillaume, Johan; Chen, Ling-chun; Teruel, Mary N.; Wandless, Thomas J.

doi:10.1074/jbc.m113.499350

Cited by 72 publications

(80 citation statements)

References 68 publications

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“…Hul5 also promotes resistance to heat stress and is a major mediator of ubiquitination under these conditions (128). Hul5 and Ube3c exert a positive effect on degradation, particularly its processivity; in its absence, some substrates are degraded incompletely, resulting in the accumulation of protein fragments (129–132). The basis for these effects may be the capacity of Hul5 to add ubiquitin promiscuously to proteasome-bound ubiquitinated proteins (124).…”

Section: Regulation Of Proteasome Activitymentioning

confidence: 99%

Gates, Channels, and Switches: Elements of the Proteasome Machine

Finley

Chen

Walters

2016

Trends in Biochemical Sciences

236

216

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The proteasome has emerged as an intricate machine that has dynamic mechanisms to regulate the timing of its activity, its selection of substrates, and its processivity. The 19-subunit regulatory particle (RP) recognizes ubiquitinated proteins, removes ubiquitin, and injects the target protein into the proteolytic chamber of the core particle (CP) via a narrow channel. Translocation into the CP requires substrate unfolding, which is achieved through mechanical force applied by a hexameric ATPase ring of the RP. Recent cryo-electron microscopy studies have defined distinct conformational states of the RP, providing illustrative snapshots of what appear to be progressive steps of substrate engagement. Here, we bring together this new information with molecular analyses to describe the principles of proteasome activity and regulation.

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Section: Regulation Of Proteasome Activitymentioning

confidence: 99%

Gates, Channels, and Switches: Elements of the Proteasome Machine

Finley

Chen

Walters

2016

Trends in Biochemical Sciences

236

216

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“…UBE3C is found at the proteasome where it functions as an E4 to extend short Ub chains on difficult‐to‐degrade substrates . The fact that His‐UBE2D2‐ABP can efficiently label UBE3C, but not proteasomal DUBs yUbp6, UCH37 or yRpn8–11, suggests that these E2–Ub‐ABPs might act as specific tools to inhibit and/or detect the activity of this proteasome‐resident E3 ubiquitin ligase.…”

Section: Discussionmentioning

confidence: 99%

“…Ub-VME this study strates. [51,54,55] The fact that His-UBE2D2-ABP can efficiently label UBE3C,b ut not proteasomal DUBs yUbp6,U CH37o r yRpn8-11, suggests that these E2-Ub-ABPs might act as specific tools to inhibita nd/ord etect the activity of this proteasome-resident E3 ubiquitin ligase. Furthermore, we have validated the use of ABPs in cell lysate.…”

Section: Nedd4mentioning

confidence: 99%

Activity‐Based Probes for HECT E3 Ubiquitin Ligases

2017

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Activity‐based probes (ABPs) have been used to dissect the biochemical/structural properties and cellular functions of deubiquitinases. However, their utility in studying cysteine‐based E3 ubiquitin ligases has been limited. In this study, we evaluate the use of ubiquitin‐ABPs (Ub‐VME and Ub‐PA) and a novel set of E2–Ub‐ABPs on a panel of HECT E3 ubiquitin ligases. Our in vitro data show that ubiquitin‐ABPs can label HECT domains. We also provide the first evidence that, in addition to the RBR E3 ubiquitin ligase Parkin, E2–Ub‐ABPs can also label the catalytic HECT domains of NEDD4, UBE3C, and HECTD1. Importantly, the endogenous proteasomal E3 ligase UBE3C was also successfully labelled by Ub‐PA and His‐UBE2D2–Ub‐ABP in lysate of cells grown under basal conditions. Our findings provide novel insights into the use of ABPs for the study of HECT E3 ubiquitin ligases.

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“…UBE3C, identified in the GFP u* CRISPR screen ( Fig. 3) codes for a proteasome-associated HECT domain Ub ligase that, like its yeast ortholog Hul5, is thought to function as an "E4", extending preexisting Ub chains on substrates, an activity proposed to antagonize proteasome-associated DUBs and to promote degradative processivity (Aviram and Kornitzer, 2010;Chu et al, 2013;Crosas et al, 2006;Kohlmann et al, 2008). Impaired GFP u* degradation in UBE3C KO cells was rescued by reintroducing wild-type UBE3C, but not a catalytically inactive variant (UBE3C C1051A ), confirming that E3 ligase activity of UBE3C is required for efficient GFP u* turnover ( Fig.…”

Section: Er and Cytosolic Ups Machinery Conjugates Heterotypic Ubiquimentioning

confidence: 99%

Parallel genome-wide CRISPR analysis identifies a role for heterotypic ubiquitin chains in ER-associated degradation

Zhang

et al. 2018

Preprint

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2 SummaryThe ubiquitin proteasome system (UPS) maintains the integrity of the proteome and controls the abundance of key regulators of cellular function by selective protein degradation, but how foldingdefective proteins in the secretory system are selected from the large and diverse constellation of membrane and secretory proteins and efficiently delivered to proteasomes in the cytosol is not well understood. To determine the basis of substrate selectivity in human cells, we developed a transcriptional shut off approach to conduct parallel, unbiased, genome-wide CRISPR analysis of structurally and topologically diverse ER-associated degradation (ERAD) clients. Highly quantitative screen metrics allowed precise dissection of entire pathways, enabling identification of unique substrate-specific combinations of recognition and ubiquitin conjugation modules. Our analysis identified cytosolic ubiquitin conjugating machinery that has not been previously linked to ERAD but collaborates with membrane-integrated ubiquitin ligases to conjugate branched or mixed ubiquitin chains to promote efficient and processive substrate degradation.All rights reserved. No reuse allowed without permission.

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The E3 Ubiquitin Ligase UBE3C Enhances Proteasome Processivity by Ubiquitinating Partially Proteolyzed Substrates

Cited by 72 publications

References 68 publications

Gates, Channels, and Switches: Elements of the Proteasome Machine

Gates, Channels, and Switches: Elements of the Proteasome Machine

Activity‐Based Probes for HECT E3 Ubiquitin Ligases

Parallel genome-wide CRISPR analysis identifies a role for heterotypic ubiquitin chains in ER-associated degradation

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