Schülein-Völk Christina, Wolf Elmar, Zhu Jing, Xu Wenshan, Taranets Lyudmyla, Hellmann Andreas, Jänicke Laura A, Diefenbacher Markus E, Behrens Axel, Eilers Martin, Popov Nikita
Department of Biochemistry and Molecular Biology, Biozentrum, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Comprehensive Cancer Center Mainfranken and Department of Radiation Oncology, University Hospital Würzburg, Versbacher Strasse 5, 97078 Würzburg, Germany.
Cell Rep. 2014 Nov 6;9(3):1099-109. doi: 10.1016/j.celrep.2014.09.057. Epub 2014 Oct 30.
Fbw7, the substrate recognition subunit of SCF(Fbw7) ubiquitin ligase, mediates the turnover of multiple proto-oncoproteins and promotes its own degradation. Fbw7-dependent substrate ubiquitination is antagonized by the Usp28 deubiquitinase. Here, we show that Usp28 preferentially antagonizes autocatalytic ubiquitination and stabilizes Fbw7, resulting in dose-dependent effects in Usp28 knockout mice. Monoallelic deletion of Usp28 maintains stable Fbw7 but drives Fbw7 substrate degradation. In contrast, complete knockout triggers Fbw7 degradation and leads to the accumulation of Fbw7 substrates in several tissues and embryonic fibroblasts. On the other hand, overexpression of Usp28 stabilizes both Fbw7 and its substrates. Consequently, both complete loss and ectopic expression of Usp28 promote Ras-driven oncogenic transformation. We propose that dual regulation of Fbw7 activity by Usp28 is a safeguard mechanism for maintaining physiological levels of proto-oncogenic Fbw7 substrates, which is equivalently disrupted by loss or overexpression of Usp28.
Fbw7是SCF（Fbw7）泛素连接酶的底物识别亚基，介导多种原癌蛋白的周转并促进其自身降解。Fbw7依赖性底物泛素化受到Usp28去泛素酶的拮抗。在此，我们表明Usp28优先拮抗自催化泛素化并稳定Fbw7，从而在Usp28基因敲除小鼠中产生剂量依赖性效应。Usp28的单等位基因缺失维持Fbw7稳定，但驱动Fbw7底物降解。相反，完全敲除会触发Fbw7降解，并导致Fbw7底物在多个组织和胚胎成纤维细胞中积累。另一方面，Usp28的过表达使Fbw7及其底物均稳定。因此，Usp28的完全缺失和异位表达均促进Ras驱动的致癌转化。我们提出，Usp28对Fbw7活性的双重调节是维持原癌基因Fbw7底物生理水平的一种保障机制，而Usp28的缺失或过表达会同等程度地破坏该机制。
