MdmX is a substrate for the deubiquitinating enzyme USP2a

Allende-Vega, Nerea; Sparks, Alison; Lane, David P.; Saville, Mark K.

doi:10.1038/onc.2009.330

Cited by 90 publications

(66 citation statements)

References 55 publications

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“…In addition to the NF-κB pathway, a huge and increasing number of proteins and pathways seems to be controlled by USP2, which is also deregulated in many cancers [41][42][43][44][45][46]. Our demonstration of USP2 involvement in the proteasomal degradation of Imd suggests a more extended function at the proteasome level than previously anticipated.…”

Section: Resultscontrasting

confidence: 43%

Identifying USPs regulating immune signals in

Engel

Viargues

Mortier

et al. 2014

Cell Communication and Signaling

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Background: Rapid activation of innate immune defences upon microbial infection depends on the evolutionary conserved NF-κB dependent signals which deregulation is frequently associated with chronic inflammation and oncogenesis. These signals are tightly regulated by the linkage of different kinds of ubiquitin moieties on proteins that modify either their activity or their stability. To investigate how ubiquitin specific proteases (USPs) orchestrate immune signal regulation, we created and screened a focused RNA interference library on Drosophila NF-κB-like pathways Toll and Imd in cultured S2 cells, and further analysed the function of selected genes in vivo.

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Section: Resultscontrasting

confidence: 43%

Identifying USPs regulating immune signals in

Engel

Viargues

Mortier

et al. 2014

Cell Communication and Signaling

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“…The increased stabilization of IDOL is a result of its USP2-dependent deubiquitylation, similar to what has been described for the USP2-MDM2 and USP2-MDMX complexes. 28,32 Regulation of E3 ligases by deubiquitylasemediated deubiquitylation has been previously reported and represents an emerging concept in E3 control. 17,[19][20][21] Previous reports indicated that deubiquitylases stabilize E3s by limiting their autoubiquitylation.…”

Section: Discussionmentioning

confidence: 99%

The Deubiquitylase USP2 Regulates the LDLR Pathway by Counteracting the E3-Ubiquitin Ligase IDOL

et al. 2016

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Rationale: The low-density lipoprotein (LDL) receptor (LDLR) is a central determinant of circulating LDL-cholesterol and as such subject to tight regulation. Recent studies and genetic evidence implicate the inducible degrader of the LDLR (IDOL) as a regulator of LDLR abundance and of circulating levels of LDL-cholesterol in humans. Acting as an E3-ubiquitin ligase, IDOL promotes ubiquitylation and subsequent lysosomal degradation of the LDLR. Consequently, inhibition of IDOL-mediated degradation of the LDLR represents a potential strategy to increase hepatic LDL-cholesterol clearance. Objective: To establish whether deubiquitylases counteract IDOL-mediated ubiquitylation and degradation of the LDLR. Methods and Results: Using a genetic screening approach, we identify the ubiquitin-specific protease 2 (USP2) as a post-transcriptional regulator of IDOL-mediated LDLR degradation. We demonstrate that both USP2 isoforms, USP2-69 and USP2-45, interact with IDOL and promote its deubiquitylation. IDOL deubiquitylation requires USP2 enzymatic activity and leads to a marked stabilization of IDOL protein. Paradoxically, this also markedly attenuates IDOL-mediated degradation of the LDLR and the ability of IDOL to limit LDL uptake into cells. Conversely, loss of USP2 reduces LDLR protein in an IDOL-dependent manner and limits LDL uptake. We identify a tri-partite complex encompassing IDOL, USP2, and LDLR and demonstrate that in this context USP2 promotes deubiquitylation of the LDLR and prevents its degradation. Conclusions: Our findings identify USP2 as a novel regulator of lipoprotein clearance owing to its ability to control ubiquitylation-dependent degradation of the LDLR by IDOL.

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“…99 MDMX, another MDM2-like p53 repressor, is also a USP2a substrate. 100 USP2a, therefore, is a A20 deficient mice, which exhibit spontaneous inflammation and premature death. 122 Recent studies have, not surprisingly, identified A20 as a crucial tumor suppressor gene.…”

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confidence: 99%