Autoregulation of the 26S proteasome by in situ ubiquitination

Jacobson, Andrew D.; MacFadden, Andrea; Wu, Zhiping; Peng, Junmin; Liu, Changwei

doi:10.1091/mbc.e13-10-0585

Cited by 66 publications

(84 citation statements)

References 59 publications

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“…UBE3A physically associates with the proteasome (24)(25)(26), and this association can be reversibly altered by certain stimuli (23). To evaluate whether T485 phosphorylation affects the association of UBE3A with the proteasome, we isolated UBE3A protein complexes from HEK293T cells overexpressing LD versions of UBE3A T485A , which cannot be phosphorylated, and UBE3A T485E , a mutant that mimics phosphorylation.…”

Section: Ube3amentioning

confidence: 99%

“…S4). We were particularly interested in PSMD4, as PSMD4 is a wellcharacterized UBE3A substrate (6,25,26,29). However, PSMD4 failed to reduce Wnt pathway activation in UBE3A T485A -expressing cells at the 1:1 or 1:2 transfection ratio ( Fig.…”

Section: Ube3amentioning

confidence: 99%

“…UBE3A inhibits proteasome function and stabilizes β-catenin Several groups found that WT UBE3A inhibits the proteasome in cells (25,34). To determine if UBE3A T485A similarly affected proteasome activity, we transfected HEK293T cells with UBE3A T485A or UBE3A T485E mutants along with a destabilized G76V-Ubiquitin(Ub)-GFP fusion reporter protein and mCherry as the normalization control.…”

Section: Ube3amentioning

confidence: 99%

“…It is well-known that UBE3A reversibly associates with the proteasome and impacts its processivity (23)(24)(25)(26)(27). Moreover, proteasome subunits and proteasome-associated proteins physically interact with and are ubiquitinated by UBE3A (28)(29)(30)(31)(32)(33)(34).…”

mentioning

confidence: 99%

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The autism-linked UBE3A T485A mutant E3 ubiquitin ligase activates the Wnt/β-catenin pathway by inhibiting the proteasome

Paranjape

Walker

et al. 2017

Journal of Biological Chemistry

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UBE3A is a HECT domain E3 ubiquitin ligase whose dysfunction is linked to autism, Angelman syndrome, and cancer. Recently, we characterized a de novo autism-linked UBE3A mutant (UBE3A T485A ) that disrupts phosphorylation control of UBE3A activity. Through quantitative proteomics and reporter assays, we found that the UBE3A T485A protein ubiquitinates multiple proteasome subunits, reduces proteasome subunit abundance and activity, stabilizes nuclear β-catenin, and stimulates canonical Wnt signaling more effectively than wild-type UBE3A. We also found that UBE3A T485A activates Wnt signaling to a greater extent in cells with low levels of ongoing Wnt signaling, suggesting that cells with low basal Wnt activity are particularly vulnerable to UBE3A T485A mutation. Ligase-dead UBE3A did not stimulate Wnt pathway activation. Overexpression of several proteasome subunits reversed the effect of UBE3A T485A on Wnt signaling. We also observed that subunits that interact with UBE3A and affect Wnt signaling are located along one side of the 19S regulatory particle, indicating a previously unrecognized spatial organization to the proteasome. Altogether, our findings indicate that UBE3A regulates Wnt signaling in a cell context-dependent manner and that an autism-linked mutation exacerbates these signaling effects. Our study has broad implications for human disorders associated with UBE3A gain or lossof-function, and suggest that dysfunctional UBE3A might affect additional proteins and pathways that are sensitive to proteasome activity.

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Section: Ube3amentioning

confidence: 99%

Section: Ube3amentioning

confidence: 99%

Section: Ube3amentioning

confidence: 99%

mentioning

confidence: 99%

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The autism-linked UBE3A T485A mutant E3 ubiquitin ligase activates the Wnt/β-catenin pathway by inhibiting the proteasome

Paranjape

Walker

et al. 2017

Journal of Biological Chemistry

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“…It may be that the key Ube3a substrates have not yet been identified or, more likely, that the disruption of Ube3A leads to a multiplicative effect involving multiple downstream targets. Indeed, recent in vitro studies reveal that Ube3a promotes the ubiquitination of the 26S proteasome itself, suggesting that it can have a significant impact on overall UPS function (Jacobson et al 2014).…”

Section: Ups Mutations In Asd/idmentioning

confidence: 99%

Perturbed proteostasis in autism spectrum disorders

Louros

Osterweil

2016

Journal of Neurochemistry

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Dynamic changes in synaptic strength rely on de novo protein synthesis and protein degradation by the ubiquitin proteasome system (UPS). Disruption of either of these cellular processes will result in significant impairments in synaptic plasticity and memory formation. Mutations in several genes encoding regulators of mRNA translation and members of the UPS have been associated with an increased risk for the development of autism spectrum disorders. It is possible that these mutations result in a similar imbalance in protein homeostasis (proteostasis) at the synapse. This review will summarize recent work investigating the role of the UPS in synaptic plasticity at glutamatergic synapses, and propose that dysfunctional proteostasis is a common consequence of several genetic mutations linked to autism spectrum disorders.

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The 19S proteasome subunit Rpt5 reversibly associates with cold‐stable microtubules in glial cells at low temperatures

Flores-Martín

Palandri

et al. 2022

FEBS Letters

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The ubiquitin–proteasome system (UPS) degrades intracellular proteins through the 26S proteasome. We analysed how cold stress affects the UPS in glial cells. Together with a reduction in the 20S proteolytic activity and increased levels of polyubiquitinated proteins, exposure of glial cell cultures to cold induces a partial disassembly of the 26S proteasome. In particular, we found that Rpt5, a subunit of the 19S proteasome, relocates to cold‐stable microtubules, although no apparent cytoskeletal redistribution was detected for other analysed subunits of the 19S or 20S complexes. Furthermore, we demonstrate that both the expression of the microtubule‐associated protein MAP6 and the post‐translational acetylation of α‐tubulin modulate the association of Rpt5 with microtubules. This reversible association could be related to functional preservation of the proteolytic complex during cold stress.

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Autoregulation of the 26S proteasome by in situ ubiquitination

Cited by 66 publications

References 59 publications

The autism-linked UBE3A T485A mutant E3 ubiquitin ligase activates the Wnt/β-catenin pathway by inhibiting the proteasome

The autism-linked UBE3A T485A mutant E3 ubiquitin ligase activates the Wnt/β-catenin pathway by inhibiting the proteasome

Perturbed proteostasis in autism spectrum disorders

The 19S proteasome subunit Rpt5 reversibly associates with cold‐stable microtubules in glial cells at low temperatures

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