Abstract
The ubiquitin-specific protease USP7 stabilizes both Mdm2 and p53 by removing ubiquitins, hence playing an important enzymatic role in the p53-Mdm2 pathway. However, it is poorly understood how USP7 executes its dual-stabilization effect on Mdm2 and p53 in cellular context. Here, we report that STIP is a novel macromolecular scaffold that links USP7 to the p53-Mdm2 pathway. STIP and a fraction of USP7 interact and constitutively colocalize in nucleoplasma. Overexpression of STIP stabilizes Mdm2 and p53, whereas downregulation of STIP decreases Mdm2 and p53 levels. The effect of STIP on Mdm2 and p53 depends on USP7 function as a deubiquitinating enzyme. Furthermore, we demonstrate that STIP mediates the assembly of two separate ternary protein complexes in vivo as STIP-USP7-Mdm2 and STIP-USP7-p53, which facilitates USP7-mediated stabilization of Mdm2 and p53. Collectively, these results pinpoint a new molecular function of STIP and reveal a novel mechanism whereby USP7 executes its dual-stabilization effect on Mdm2 and p53 via STIP scaffolding.
Highlights
STIP interacts with USP7 and the two proteins colocalize to the nucleoplasma in vivo
We found that the USP7-Mdm2 or USP7-p53 interactions were significantly reduced in STIP short hairpin RNA (shRNA)-treated U2OS cells by co-IP (Figure 5C)
Because STIP and USP7 interact in vivo and display similar effects toward Mdm2 or p53, we considered whether STIP regulation of Mdm2 and p53 stability may be mediated through USP7
Summary
P53 is a multi-talented tumor suppressor, yet the most frequently mutated gene in human cancers [1, 2]. Given that STIP is not known to possess any enzymatic activity, we conclude that STIP functions as a nuclear scaffold that enables protein complex assembly and plays a critical role in the p53-Mdm axis by facilitating USP7-mediated stabilization of Mdm and p53. These results pinpoint a new molecular function of STIP and reveal an important missing piece in the regulation of Mdm and p53 stability by USP7 in cellular context
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