Abstract
The overexpression of Mdm2 has been linked to the loss of p53 tumour suppressor activity in several human cancers. Here, we present results suggesting that ubiquitin-specific peptidase 48 (USP48), a deubiquitinase that has been linked in previous reports to the NF-κB signaling pathway, is a novel Mdm2 binding partner that promotes Mdm2 stability and enhances Mdm2-mediated p53 ubiquitination and degradation. In contrast to other deubiquitinating enzymes (DUBs) that have been previously implicated in the regulation of Mdm2 protein stability, USP48 did not induce Mdm2 stabilization by significantly reducing Mdm2 ubiquitination levels. Moreover, two previously characterized USP48 mutants lacking deubiquitinase activity were also capable of efficiently stabilizing Mdm2, indicating that USP48 utilizes a non-canonical, deubiquitination-independent mechanism to promote Mdm2 oncoprotein stability. This study represents, to the best of our knowledge, the first report suggesting DUB-mediated target protein stabilization that is independent of its deubiquitinase activity. In addition, our results suggest that USP48 might represent a new mechanism of crosstalk between the NF-κB and p53 stress response pathways.
Highlights
DNA damage, USP10 can translocate to the nucleus and contribute to p53 activation[13,14]
Given that NF-κB signaling can have a strong impact on the p53 pathway by controlling the cellular levels of Mdm[2] ubiquitin ligase[25,26,27], we sought to analyze the possible role of USP48 in the regulation of the p53 pathway
The cycloheximide chase experiments showed that both USP48 mutants were capable of promoting the stability of Mdm[2] protein in cells (Fig. 5C). These results clearly showed that the stabilization of Mdm[2] by USP48 did not depend on its deubiquitinase activity
Summary
DNA damage, USP10 can translocate to the nucleus and contribute to p53 activation[13,14]. USP24 is another DUB that was recently implicated in the regulation of the p53 pathway and in the cellular response to DNA damage by deubiquitinating p5316 In contrast to these deubiquitinases that target p53, USP2a was shown to deubiquitinate and stabilize only Mdm[2] and Mdm[4] while exhibiting no deubiquitinase activity toward p5317,18. The ectopic expression of USP2a leads to Mdm[2] and Mdm[4] stabilization and promotes p53 degradation, and USP2a knockdown increases cellular p53 protein levels and transcriptional activity In addition to these DUBs that directly target the main players in the p53 pathway, several USPs have been shown to modulate the p53 pathway activity by targeting other p53 regulators, rather than Mdm[2]. Our results suggest that USP48 is a new binding partner for Mdm[2] and plays a direct role in the regulation of Mdm[2] stability via a non-canonical, deubiquitinase activity-independent mechanism
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