Trimming of ubiquitin chains by proteasome-associated deubiquitinating enzymes.
Trimming of ubiquitin chains by proteasome-associated deubiquitinating enzymes.
复制标题
DOI：
10.1074/mcp.r110.003871
复制
发表时间：
2011-05-01
期刊：
影响因子：
--
通讯作者：
Finley, Daniel
中科院分区：
文献类型：
--
作者：
Lee, Min Jae;Lee, Byung-Hoon;Finley, Daniel
蛋白酶体通常通过其多泛素链识别底物，然后通过atp依赖性的展开和底物从调节颗粒转运到待降解的蛋白水解核心颗粒。底物结合的泛素基团大部分不会被递送到核心颗粒并与底物一起分解，而是作为完整的自由泛素和泛素链被回收。蛋白酶体上的底物去泛素化是由三种不同的与调节颗粒相关的去泛素化酶介导的：RPN11、UCH37和USP14。RPN11在与底物连接的泛素链的底部切割，而UCH37和USP14则通过从远端分解泛素链来逐步从底物中去除泛素。与UCH37和USP14相比，RPN11表现出降解偶联活性；rpn11介导的去泛素化明显延迟，直到蛋白酶体致力于降解底物。因此，rpn11介导的去泛素化促进了底物的降解。相反，在承诺之前去除泛素可以通过促进底物与蛋白酶体分离来对抗底物降解。新出现的证据表明，USP14和UCH37都可以通过这种方式抑制底物降解。一项研究表明，小分子USP14抑制剂可以增强细胞中的蛋白酶体功能，这与该模型一致。增强蛋白质降解可能对涉及作为蛋白酶体底物的有毒蛋白质的疾病具有潜在的治疗应用。然而，底物对蛋白酶体去泛素化酶抑制的反应性可能有很大差异。这种底物特异性及其机制基础应在未来的研究中加以解决。
The proteasome generally recognizes substrate via its multiubiquitin chain followed by ATP-dependent unfolding and translocation of the substrate from the regulatory particle into the proteolytic core particle to be degraded. Substrate-bound ubiquitin groups are for the most part not delivered to the core particle and broken down together with substrate but instead recovered as intact free ubiquitin and ubiquitin chains. Substrate deubiquitination on the proteasome is mediated by three distinct deubiquitinating enzymes associated with the regulatory particle: RPN11, UCH37, and USP14. RPN11 cleaves at the base of the ubiquitin chain where it is linked to the substrate, whereas UCH37 and apparently USP14 mediate a stepwise removal of ubiquitin from the substrate by disassembling the chain from its distal tip. In contrast to UCH37 and USP14, RPN11 shows degradation-coupled activity; RPN11-mediated deubiquitination is apparently delayed until the proteasome is committed to degrade the substrate. Accordingly, RPN11-mediated deubiquitination promotes substrate degradation. In contrast, removal of ubiquitin prior to commitment could antagonize substrate degradation by promoting substrate dissociation from the proteasome. Emerging evidence suggests that USP14 and UCH37 can both suppress substrate degradation in this way. One line of study has shown that small molecule USP14 inhibitors can enhance proteasome function in cells, which is consistent with this model. Enhancing protein degradation could potentially have therapeutic applications for diseases involving toxic proteins that are proteasome substrates. However, the responsiveness of substrates to inhibition of proteasomal deubiquitinating enzymes may vary substantially. This substrate specificity and its mechanistic basis should be addressed in future studies.