蛋白质稳态(proteostasis)是细胞借助多层次质量控制网络,维持蛋白质组稳定性与功能完整性的核心生物学过程。泛素特异性蛋白酶7(ubiquitin specific protease 7, USP7)作为泛素化调控通路中的关键分子,其表达异常或活性失调会通过改变...蛋白质稳态(proteostasis)是细胞借助多层次质量控制网络,维持蛋白质组稳定性与功能完整性的核心生物学过程。泛素特异性蛋白酶7(ubiquitin specific protease 7, USP7)作为泛素化调控通路中的关键分子,其表达异常或活性失调会通过改变底物蛋白的泛素化修饰状态,驱动肿瘤的发生与进展,已成为肿瘤精准治疗领域的重要研究靶点。本文系统概述了USP7的结构特征、对底物蛋白的稳态调控作用及其在肿瘤发展中的生物学功能,重点围绕近年来基于USP7的肿瘤治疗策略展开综述:包括小分子抑制剂的开发进展、蛋白降解靶向嵌合体技术的应用,以及去泛素化酶靶向嵌合体等新型策略的探索。该综述为靶向USP7的抗肿瘤药物研发提供了系统性的理论参考与前沿研究方向。展开更多
泛素特异性蛋白酶7(ubiquitin-specific protease 7,USP7),也称为疱疹病毒属伴随的泛素特异性的蛋白酶(herpesvirus-associated ubiquitin specific protease,HAUSP),是泛素特异性修饰酶家族(ubiquitin specific processing enzymes,UB...泛素特异性蛋白酶7(ubiquitin-specific protease 7,USP7),也称为疱疹病毒属伴随的泛素特异性的蛋白酶(herpesvirus-associated ubiquitin specific protease,HAUSP),是泛素特异性修饰酶家族(ubiquitin specific processing enzymes,UBPs)的成员之一。USP7蛋白作为一个去泛素化蛋白酶,对卷入细胞周期、癌基因和抑癌基因等相关蛋白具有重要的调控作用。所以,USP7是一个极具前景的抗癌靶点。本文拟就USP7蛋白与肿瘤的关系的研究进展进行综述。展开更多
Molecular glues are typically small chemical molecules that act at the interface between a target protein and degradation machinery to trigger ternary complex formation.Identifying molecular glues is challenging.There...Molecular glues are typically small chemical molecules that act at the interface between a target protein and degradation machinery to trigger ternary complex formation.Identifying molecular glues is challenging.There is a scarcity of target-specific upregulating molecular glues,which are highly anticipated for numerous targets,including P53.P53 is degraded in proteasomes through polyubiquitination by specific E3 ligases,whereas deubiquitinases(DUBs)remove polyubiquitination conjugates to counteract these E3ligases.Thus,small-molecular glues that enhance P53 anchoring to DUBs may stabilize P53 through deubiquitination.Here,using small-molecule microarray-based technology and unbiased screening,we identified three potential molecular glues that may tether P53 to the DUB,USP7,and elevate the P53 level.Among the molecular glues,bromocriptine(BC)is an FDA-approved drug with the most robust effects.BC was further verified to increase P53 stability via the predicted molecular glue mechanism engaging USP7.Consistent with P53 upregulation in cancer cells,BC was shown to inhibit the proliferation of cancer cells in vitro and suppress tumor growth in a xenograft model.In summary,we established a potential screening platform and identified potential molecular glues upregulating P53.Similar strategies could be applied to the identification of other types of molecular glues that may benefit drug discovery and chemical biology studies.展开更多
Targeting immune checkpoints such as programmed cell death protein 1(PD-1)and programmed death ligand-1(PD-L1)have been approved for treating melanoma,gastric cancer(GC)and bladder cancer with clinical benefit.Neverth...Targeting immune checkpoints such as programmed cell death protein 1(PD-1)and programmed death ligand-1(PD-L1)have been approved for treating melanoma,gastric cancer(GC)and bladder cancer with clinical benefit.Nevertheless,many patients failed to respond to anti-PD-1/PD-L1 treatment,so it is necessary to seek an alternative strategy for traditional PD-1/PD-L1 targeting immunotherapy.Here with the data from The Cancer Genome Atlas(TCGA)and our in-house tissue library,PD-L1 expression was found to be positively correlated with the expression of ubiquitin-specific processing protease 7(USP7)in GC.Furthermore,USP7 directly interacted with PD-L1 in order to stabilize it,Gastric cancer;Immunosuppression;Cancer biologywhile abrogation of USP7 attenuated PD-L1/PD-1 interaction and sensitized cancer cells to T cell killing in vitro and in vivo.Besides,USP7 inhibitor suppressed GC cells proliferation by stabilizing P53 in vitro and in vivo.Collectively,our findings indicate that in addition to inhibiting cancer cells proliferation,USP7 inhibitor can also downregulate PD-L1 expression to enhance anti-tumor immune response simultaneously.Hence,these data posit USP7 inhibitor as an anti-proliferation agent as well as a novel therapeutic agent in PD-L1/PD-1 blockade strategy that can promote the immune response of the tumor.展开更多
文摘蛋白质稳态(proteostasis)是细胞借助多层次质量控制网络,维持蛋白质组稳定性与功能完整性的核心生物学过程。泛素特异性蛋白酶7(ubiquitin specific protease 7, USP7)作为泛素化调控通路中的关键分子,其表达异常或活性失调会通过改变底物蛋白的泛素化修饰状态,驱动肿瘤的发生与进展,已成为肿瘤精准治疗领域的重要研究靶点。本文系统概述了USP7的结构特征、对底物蛋白的稳态调控作用及其在肿瘤发展中的生物学功能,重点围绕近年来基于USP7的肿瘤治疗策略展开综述:包括小分子抑制剂的开发进展、蛋白降解靶向嵌合体技术的应用,以及去泛素化酶靶向嵌合体等新型策略的探索。该综述为靶向USP7的抗肿瘤药物研发提供了系统性的理论参考与前沿研究方向。
文摘泛素特异性蛋白酶7(ubiquitin-specific protease 7,USP7),也称为疱疹病毒属伴随的泛素特异性的蛋白酶(herpesvirus-associated ubiquitin specific protease,HAUSP),是泛素特异性修饰酶家族(ubiquitin specific processing enzymes,UBPs)的成员之一。USP7蛋白作为一个去泛素化蛋白酶,对卷入细胞周期、癌基因和抑癌基因等相关蛋白具有重要的调控作用。所以,USP7是一个极具前景的抗癌靶点。本文拟就USP7蛋白与肿瘤的关系的研究进展进行综述。
基金supported by the National Natural Science Foundation of China(82050008,92049301,81925012,32200797,32271510,32200602,and 82030106)the Science and Technology Commission of Shanghai Municipality(20JC1410900)+3 种基金Shanghai Municipal Science and Technology Key Laboratory Project(23dz2260100)the Innovation Program of Shanghai Municipal Education Commission(2021-01-07-00-07-E00074)the Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)the China Postdoctoral Science Foundation(BX20200093 and 2021M690038)。
文摘Molecular glues are typically small chemical molecules that act at the interface between a target protein and degradation machinery to trigger ternary complex formation.Identifying molecular glues is challenging.There is a scarcity of target-specific upregulating molecular glues,which are highly anticipated for numerous targets,including P53.P53 is degraded in proteasomes through polyubiquitination by specific E3 ligases,whereas deubiquitinases(DUBs)remove polyubiquitination conjugates to counteract these E3ligases.Thus,small-molecular glues that enhance P53 anchoring to DUBs may stabilize P53 through deubiquitination.Here,using small-molecule microarray-based technology and unbiased screening,we identified three potential molecular glues that may tether P53 to the DUB,USP7,and elevate the P53 level.Among the molecular glues,bromocriptine(BC)is an FDA-approved drug with the most robust effects.BC was further verified to increase P53 stability via the predicted molecular glue mechanism engaging USP7.Consistent with P53 upregulation in cancer cells,BC was shown to inhibit the proliferation of cancer cells in vitro and suppress tumor growth in a xenograft model.In summary,we established a potential screening platform and identified potential molecular glues upregulating P53.Similar strategies could be applied to the identification of other types of molecular glues that may benefit drug discovery and chemical biology studies.
基金supported by National Natural Science Foundation of China(Project No.81602961 for Yichao ZhengNos.81430085,81773562,and 82020108030 for Hongmin Liu)+2 种基金National Key Research Program of Proteins(Nos.2016YFA0501800 and 2018YFE0195100 for Hongmin Liu,China)Key Research Program of Henan Province(No.161100310100,for Hongmin Liu,China)Science and Technology Innovation Talents of Henan Provincial Education Department(19IRTSTHN001,China)。
文摘Targeting immune checkpoints such as programmed cell death protein 1(PD-1)and programmed death ligand-1(PD-L1)have been approved for treating melanoma,gastric cancer(GC)and bladder cancer with clinical benefit.Nevertheless,many patients failed to respond to anti-PD-1/PD-L1 treatment,so it is necessary to seek an alternative strategy for traditional PD-1/PD-L1 targeting immunotherapy.Here with the data from The Cancer Genome Atlas(TCGA)and our in-house tissue library,PD-L1 expression was found to be positively correlated with the expression of ubiquitin-specific processing protease 7(USP7)in GC.Furthermore,USP7 directly interacted with PD-L1 in order to stabilize it,Gastric cancer;Immunosuppression;Cancer biologywhile abrogation of USP7 attenuated PD-L1/PD-1 interaction and sensitized cancer cells to T cell killing in vitro and in vivo.Besides,USP7 inhibitor suppressed GC cells proliferation by stabilizing P53 in vitro and in vivo.Collectively,our findings indicate that in addition to inhibiting cancer cells proliferation,USP7 inhibitor can also downregulate PD-L1 expression to enhance anti-tumor immune response simultaneously.Hence,these data posit USP7 inhibitor as an anti-proliferation agent as well as a novel therapeutic agent in PD-L1/PD-1 blockade strategy that can promote the immune response of the tumor.
