MassIVE MSV000087940

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USP7 substrates identified by proteomics analysis reveal the specificity of USP7 and its inhibitors

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Description

Deubiquitylating enzymes (DUBs) remove ubiquitin chains from proteins and regulate protein stability and function. USP7 is one of the most compressively studied DUBs. Since USP7 has several well-known substrates important for cancer progression, such as MDM2, N-MYC and PTEN, USP7 becomes a promising drug target. However, systematic identification of USP7 substrates have not yet been performed. In this study, we carried out proteome profiling with label-free quantification using control and single/double KO cells of USP7 and its closest homolog USP47. Our proteome profiling for the first time reveal the proteome changes caused by USP7 and/or USP47 deletion. Combining protein profiling, transcriptome analysis and tandem-affinity purification of USP7-associated proteins, we compiled a list of 20 high-confidence USP7 substrates, which include known and novel USP7 substrates. We experimentally validated MGA and PHIP as new substrates of USP7. Further, we showed that MGA deletion partially phenocopied proliferation defect observed in cells with USP7 deletion. Additionally, we established that USP7 deletion repress interferon gamma response. Moreover, we showed that the cytotoxicity of USP7 inhibitors were independent of USP7. In conclusion, our study is the first proteome-wide analysis of potential USP7 substrates, which provides a resource for further functional studies. [doi:10.25345/C5JZ51]

Keywords: USP7 ; USP7 inhibitor ; USP47 ; Label-free quantification

Contact

Principal Investigators:
(in alphabetical order) 		Junjie Chen, The University of Texas MD Anderson Cancer Center, United States
Submitting User: Litong
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