Rudolf Virchow Center for Experimental Biomedicine, Institute for Structural Biology, University of Würzburg, 97080 Würzburg, Germany.
Department of Clinical Tumor Biology, University Hospital Tübingen, 72076 Tübingen, Germany.
Mol Cell. 2019 May 2;74(3):421-435.e10. doi: 10.1016/j.molcel.2019.02.029. Epub 2019 Mar 26.
Deubiquitinases have emerged as promising drug targets for cancer therapy. The two DUBs USP25 and USP28 share high similarity but vary in their cellular functions. USP28 is known for its tumor-promoting role, whereas USP25 is a regulator of the innate immune system and, recently, a role in tumorigenesis was proposed. We solved the structures of the catalytic domains of both proteins and established substantial differences in their activities. While USP28 is a constitutively active dimer, USP25 presents an auto-inhibited tetramer. Our data indicate that the activation of USP25 is not achieved through substrate or ubiquitin binding. USP25 cancer-associated mutations lead to activation in vitro and in vivo, thereby providing a functional link between auto-inhibition and the cancer-promoting role of the enzyme. Our work led to the identification of significant differences between USP25 and USP28 and provided the molecular basis for the development of new and highly specific anti-cancer drugs.
去泛素化酶已成为癌症治疗有前途的药物靶点。两种 DUBs（USP25 和 USP28）具有高度相似性，但在细胞功能上有所不同。USP28 以其促进肿瘤的作用而闻名，而 USP25 是先天免疫系统的调节剂，最近也提出了其在肿瘤发生中的作用。我们解决了这两种蛋白质的催化结构域的结构，并确定了它们在活性上的显著差异。虽然 USP28 是一种组成性活性二聚体，但 USP25 呈现出自动抑制的四聚体。我们的数据表明，USP25 的激活不是通过底物或泛素结合来实现的。USP25 癌症相关突变导致体外和体内激活，从而为酶的自动抑制和促进癌症的作用之间提供了功能联系。我们的工作导致了 USP25 和 USP28 之间的显著差异，并为开发新的和高度特异性的抗癌药物提供了分子基础。
