USP7 substrates identified by proteomics analysis reveal the specificity of USP7
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA752331 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15349300_1.fastq.gz | Fastqsanger.gz | |||
| SRR15349300_2.fastq.gz | Fastqsanger.gz | |||
| SRR15349301_1.fastq.gz | Fastqsanger.gz | |||
| SRR15349301_2.fastq.gz | Fastqsanger.gz | |||
| SRR15349302_1.fastq.gz | Fastqsanger.gz |
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Project description:Deubiquitylating enzymes (DUBs) remove ubiquitin chains from proteins and regulate protein stability and function. USP7 is one of the most extensively studied DUBs, since USP7 has several well-known substrates important for cancer progression, such as MDM2, N-MYC, and PTEN. Thus, USP7 is a promising drug target. However, systematic identification of USP7 substrates has not yet been performed. In this study, we carried out proteome profiling with label-free quantification in control and single/double-KO cells of USP7and its closest homolog, USP47 Our proteome profiling for the first time revealed the proteome changes caused by USP7 and/or USP47 depletion. Combining protein profiling, transcriptome analysis, and tandem affinity purification of USP7-associated proteins, we compiled a list of 20 high-confidence USP7 substrates that includes known and novel USP7 substrates. We experimentally validated MGA and PHIP as new substrates of USP7. We further showed that MGA deletion reduced cell proliferation, similar to what was observed in cells with USP7 deletion. In conclusion, our proteome-wide analysis uncovered potential USP7 substrates, providing a resource for further functional studies.
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Project description:Deubiquitylating enzymes (DUBs) counteract ubiquitylation to control stability or activity of substrates. Identification of DUB substrates is challenging because multiple DUBs can act on the same substrate, thwarting genetic approaches. Here, we circumvent redundancy by chemically inhibiting multiple DUBs simultaneously in Xenopus egg extract. We discovered a set of proteins that depends on DUBs for their stability and we confirmed their DUB-dependent regulation with human orthologs, demonstrating evolutionary conservation. We next extended this approach, developing a new method to profile DUB specificity. By adding recombinant DUBs to extract where DUB activity was broadly inhibited, but ubiquitylation and degradation were active at physiological rates, we profiled the ability of DUBs to rescue degradation of these new substrates. We found that USP7 has a unique ability to broadly antagonize their degradation. Together, we identify novel DUB substrates and present an approach to characterize DUB specificity that overcomes challenges posed by DUB redundancy.
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