Specificity profiling of deubiquitylases against endogenously generated ubiquitin-protein conjugates

被引:4
|
作者
Rossio, Valentina [1 ]
Paulo, Joao A. [1 ]
Liu, Xinyue [1 ]
Gygi, Steven P. [1 ]
King, Randall W. [1 ]
机构
[1] Harvard Med Sch, Blavatnik Inst, Dept Cell Biol, Boston, MA 02115 USA
关键词
MECHANISMS; PROTEASOME; CHAIN; CYLD;
D O I
10.1016/j.chembiol.2024.05.001
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Deubiquitylating enzymes (DUBs) remove ubiquitin from proteins thereby regulating their stability or activity. Our understanding of DUB-substrate specificity is limited because DUBs are typically not compared to each other against many physiological substrates. By broadly inhibiting DUBs in Xenopus egg extract, we generated hundreds of ubiquitylated proteins and compared the ability of 30 DUBs to deubiquitylate them using quantitative proteomics. We identified five high-impact DUBs (USP7, USP9X, USP36, USP15, and USP24) that each reduced ubiquitylation of over 10% of the isolated proteins. Candidate substrates of high-impact DUBs showed substantial overlap and were enriched for disordered regions, suggesting this feature may promote substrate recognition. Other DUBs showed lower impact and non-overlapping specificity, targeting distinct non-disordered proteins including complexes such as the ribosome or the proteasome. Altogether our study identifies candidate DUB substrates and defines patterns of functional redundancy and specificity, revealing substrate characteristics that may influence DUB-substrate recognition.
引用
收藏
页码:1349 / 1362.e5
页数:20
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