Department of Experimental Oncology, European Institute of Oncology, 20139 Milan, Italy.
Proc Natl Acad Sci U S A. 2013 Nov 5;110(45):18168-73. doi: 10.1073/pnas.1311382110. Epub 2013 Oct 21.
The tumor suppressor VHL (von Hippel-Lindau) protein is a substrate receptor for Ubiquitin Cullin Ring Ligase complexes (CRLs), containing a BC-box domain that associates to the adaptor Elongin B/C. VHL targets hypoxia-inducible factor 1α to proteasome-dependent degradation. Gam1 is an adenoviral protein, which also possesses a BC-box domain that interacts with the host Elongin B/C, thereby acting as a viral substrate receptor. Gam1 associates with both Cullin2 and Cullin5 to form CRL complexes targeting the host protein SUMO enzyme SAE1 for proteasomal degradation. We show that Gam1 protein expression induces VHL protein degradation leading to hypoxia-inducible factor 1α stabilization and induction of its downstream targets. We also characterize the CRL-dependent mechanism that drives VHL protein degradation via proteasome. Interestingly, expression of Suppressor of Cytokine Signaling (SOCS) domain-containing viral proteins and cellular BC-box proteins leads to VHL protein degradation, in a SOCS domain-containing manner. Our work underscores the exquisite ability of viral domains to uncover new regulatory mechanisms by hijacking key cellular proteins.
抑瘤蛋白 VHL（von Hippel-Lindau）是泛素连接酶复合物（CRLs）的底物受体，包含一个与接头 Elongin B/C 结合的 BC 盒结构域。VHL 将缺氧诱导因子 1α 靶向蛋白酶体降解。Gam1 是一种腺病毒蛋白，也具有与宿主 Elongin B/C 相互作用的 BC 盒结构域，从而作为病毒底物受体。Gam1 与 Cullin2 和 Cullin5 结合形成 CRL 复合物，靶向宿主蛋白 SUMO 酶 SAE1 进行蛋白酶体降解。我们发现 Gam1 蛋白表达诱导 VHL 蛋白降解，导致缺氧诱导因子 1α 稳定并诱导其下游靶标。我们还描述了通过蛋白酶体驱动 VHL 蛋白降解的 CRL 依赖性机制。有趣的是，表达含有 SOCS 结构域的病毒蛋白和细胞内 BC 盒蛋白以含有 SOCS 结构域的方式导致 VHL 蛋白降解。我们的工作强调了病毒结构域通过劫持关键细胞蛋白来揭示新的调节机制的精湛能力。
