The ubiquitin-proteasome pathway is an important protein degradation regulation system in cells. Through polyubiquitination of the substrate protein and degradation by the proteasome, it can affect or regulate a variety of cell activities, including: gene transcription, cell cycle regulation, immune response, cell receptor function, tumor growth, and inflammatory processes. This pathway is also a dynamic two-way protein modification and regulation system. In the body, the ubiquitin ligase system (E1-E2-E3) modifies the substrate for ubiquitination. The deubiquitinating enzyme (DUB) family is responsible for hydrolyzing ubiquitin. The ester bond, peptide bond or isopeptide bond at the carboxyl end of the ubiquitin molecule specifically hydrolyzes the ubiquitin molecule from the protein or precursor protein linked with ubiquitin, which acts as deubiquitination and reverses protein degradation. Regulation, thereby affecting the function of the protein.
Deubiquitinating enzymes are a large number of protease families, mainly divided into five families, namely, ubiquitin carboxyl-terminal hydrolase (UCH) family, ubiquitin-specific protease (USP/UBP) family, Otubaim (OTU) ) Family, Josephin domain protein family and JAMM family.
The functions of deubiquitinating enzymes in cells can be roughly divided into the following categories: (1) Process ubiquitin precursors to produce free ubiquitin molecules; (2) Remove ubiquitin chains on proteins to prevent proteins from being protease The body degrades, thereby stabilizing the protein; (3) Remove the non-degradable ubiquitination signal attached to the protein; (4) Ensure the stability of the ubiquitin molecule in the cell by preventing the ubiquitin molecule from being degraded together with the substrate protein; ( 5) Participate in the disintegration of free ubiquitin chains in cells; (6) Edit the types of ubiquitin chains by cutting the ubiquitin chains.
The relationship between deubiquitinating enzymes and cell cycle regulation
The cell cycle process involves multi-level and multi-faceted regulation. As an important type of hydrolase involved in the post-translational modification of proteins, deubiquitination enzymes play an important role in the cell cycle regulation process. Deubiquitinating enzymes play different biological functions in different cycle control. The separation process of chromosomes affects the cell cycle process; USP9X and USP1 are mainly involved in the DNA damage repair process in the S phase and affect the operation of the cell cycle in the S phase, while USP9X in the G1/S phase and USP1 in the G2/M phase are promoted by other means. The cell cycle runs.
Application of non-alcoholic fatty liver (NAFLD)
Researchers found that the expression of USP14 protein in obese mice increased significantly. They used cell lines stably expressing and knocking out USP14, through the combined application of large-scale protein-protein interactionomics, quantitative proteomics, ubiquitin chemicalomics, and comprehensive bioinformatics analysis, and found that triglyceride synthesis The key enzyme-fatty acid synthase (FASN) is one of the target molecules of USP14. Studies have found that the increased expression of USP14 in obese mice can reduce the ubiquitination level of FASN, increase the stability of FASN protein, increase triglyceride synthesis, and ultimately increase the level of NAFLD.
Application in tumor
Some small molecule inhibitors have been developed, which can broadly inhibit the deubiquitination activity of USP7 without direct binding, covalent binding or non-covalent binding, thereby inducing the degradation of MDM2 and MDMX and stabilizing and activating p53. These compounds have shown anticancer effects in vivo and in vitro. Direct inhibition of the combination of USP7 with MDM2 and MDMX may be tested to develop safer and more effective cancer treatment inhibitors.
Summary of USP7’s role in cancer and known interaction partners. Orange is the main known processes and pathways of USP7 functions, and green is the interaction of known targets corresponding to these functions.