The ubiquitin-interacting motifs of S5a as a unique upstream inhibitor of the 26S proteasome

Elangovan, Muthukumar; Shin, Dong Yeon; Yoo, Yung Joon

doi:10.1016/j.bbrc.2009.08.078

Cited by 9 publications

(4 citation statements)

References 13 publications

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“…A deletion of S5a (S5aUIM) lacking the N terminus, which is required for incorporation into the proteasome 17, 39 but retaining the UIMs, further increased p53 levels compared with S5a knockdown. This mutant is able to associate with high-molecular weight conjugates of p53 (Figure 3b).…”

Section: Resultsmentioning

confidence: 99%

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The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a

et al. 2013

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p53 and its major E3 ligase Mdm2 are both ubiquitinated and targeted to the proteasome for degradation. Despite the importance of this in regulating the p53 pathway, little is known about the mechanisms of proteasomal recognition of ubiquitinated p53 and Mdm2. In this study, we show that knockdown of the proteasomal ubiquitin receptor S5a/PSMD4/Rpn10 inhibits p53 protein degradation and results in the accumulation of ubiquitinated p53. Overexpression of a dominant-negative deletion of S5a lacking its ubiquitin-interacting motifs (UIM)s, but which can be incorporated into the proteasome, also causes the stabilization of p53. Furthermore, small-interferring RNA (siRNA) rescue experiments confirm that the UIMs of S5a are required for the maintenance of low p53 levels. These observations indicate that S5a participates in the recognition of ubiquitinated p53 by the proteasome. In contrast, targeting S5a has no effect on the rate of degradation of Mdm2, indicating that proteasomal recognition of Mdm2 can be mediated by an S5a-independent pathway. S5a knockdown results in an increase in the transcriptional activity of p53. The selective stabilization of p53 and not Mdm2 provides a mechanism for p53 activation. Depletion of S5a causes a p53-dependent decrease in cell proliferation, demonstrating that p53 can have a dominant role in the response to targeting S5a. This study provides evidence for alternative pathways of proteasomal recognition of p53 and Mdm2. Differences in recognition by the proteasome could provide a means to modulate the relative stability of p53 and Mdm2 in response to cellular signals. In addition, they could be exploited for p53-activating therapies. This work shows that the degradation of proteins by the proteasome can be selectively dependent on S5a in human cells, and that this selectivity can extend to an E3 ubiquitin ligase and its substrate.

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Section: Resultsmentioning

confidence: 99%

“…There is evidence that S5a influences p53 protein expression, 38, 39 but this has not been investigated in detail. Consistent with a role in recruitment of p53 to the proteasome, knockdown of the UBA/UBL adaptor proteins hHR23A and hHR23B has been observed to cause the accumulation of p53.…”

Section: Introductionmentioning

confidence: 99%

The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a

et al. 2013

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“…S7 S8 S9 S10b in regulating protein degradation at the proteasome (Elangovan et al, 2009;Wang et al, 2005;Isasa et al, 2010). The above results suggest that E6 can potentially recognise multiple proteasome subunits, but that recognition of the S5a subunit is dependent upon E6AP.…”

Section: Hpv E6 Induces Polyubiquitination Of S5amentioning

confidence: 86%

Interaction of HPV E6 oncoproteins with specific proteasomal subunits

et al. 2013

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The Human Papillomavirus E6 oncoproteins have the capacity to target several of their cellular interacting partners for proteasome mediated degradation, and recent proteomic analyses suggest a close involvement of E6 with the cellular proteasome machinery. In this study we have performed an extensive analysis of the capacity of different E6 oncoproteins to interact with specific proteasome components. We demonstrate that multiple subunits of the proteasome can be bound by different HPV E6 oncoproteins. Furthermore, whilst most of these interactions appear independent of the E6AP ubiquitin ligase, the association of E6 with the major ubiquitin-accepting proteasome subunit, S5a, does require the presence of E6AP. One consequence of the interaction between E6/E6AP and S5a is enhanced ubiquitination of this proteasome subunit. These results suggest a complex interplay between E6 and the proteasome, only some aspects of which are dependent upon the E6AP ubiquitin ligase.

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“…This is consistent with work showing that p53 is accumulated following knockdown of S5A in a range of cell types [ 43 ]. In HPV18‐positive cells, in which HPV protein E6 and cellular E6AP mediate p53 degradation rather than MDM2 [ 44 ], S5A knockdown also increases p53 levels [ 45 ]. RAD23A directly binds to MDM2, but the impact of RAD23A or B depletion on the level of p53 varies between studies and its effect on the stability of MDM2 has not been addressed [ 46 , 47 , 48 ].…”

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confidence: 99%

Ubiquitin receptors play redundant roles in the proteasomal degradation of the p53 repressor MDM2

2022

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Much remains to be determined about the participation of ubiquitin receptors in proteasomal degradation and their potential as therapeutic targets. Suppression of the ubiquitin receptor S5A/PSMD4/hRpn10 alone stabilises p53/ TP53 but not the key p53 repressor MDM2. Here, we observed S5A and the ubiquitin receptors ADRM1/PSMD16/hRpn13 and RAD23A and B functionally overlap in MDM2 degradation. We provide further evidence that degradation of only a subset of ubiquitinated proteins is sensitive to S5A knockdown because ubiquitin receptor redundancy is commonplace. p53 can be upregulated by S5A modulation while degradation of substrates with redundant receptors is maintained. Our observations and analysis of Cancer Dependency Map (DepMap) screens show S5A depletion/loss substantially reduces cancer cell line viability. This and selective S5A dependency of proteasomal substrates make S5A a target of interest for cancer therapy.

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The ubiquitin-interacting motifs of S5a as a unique upstream inhibitor of the 26S proteasome

Cited by 9 publications

References 13 publications

The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a

The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a

Interaction of HPV E6 oncoproteins with specific proteasomal subunits

Ubiquitin receptors play redundant roles in the proteasomal degradation of the p53 repressor MDM2

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