Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, 78712, USA.
Nat Commun. 2020 Apr 24;11(1):2019. doi: 10.1038/s41467-020-16003-3.
Retinoblastoma protein (Rb) is a tumor suppressor that binds and represses E2F transcription factors. In cervical cancer cells, human papilloma virus (HPV) protein E7 binds to Rb, releasing it from E2F to promote cell cycle progression, and inducing ubiquitination of Rb. E7-mediated proteasomal degradation of Rb requires action by another protease, calpain, which cleaves Rb after Lys 810. However, it is not clear why cleavage is required for Rb degradation. Here, we report that the proteasome cannot initiate degradation efficiently on full-length Rb. Calpain cleavage exposes a region that is recognized by the proteasome, leading to rapid proteolysis of Rb. These findings identify a mechanism for regulating protein stability by controlling initiation and provide a better understanding of the molecular mechanism underlying transformation by HPV.
视网膜母细胞瘤蛋白（Rb）是一种肿瘤抑制因子，它能与 E2F 转录因子结合并抑制其活性。在宫颈癌细胞中，人乳头瘤病毒（HPV）蛋白 E7 与 Rb 结合，将其从 E2F 上释放出来，促进细胞周期进程，并诱导 Rb 的泛素化。E7 通过另一种蛋白酶钙蛋白酶介导的 Rb 蛋白水解需要发挥作用，钙蛋白酶在赖氨酸 810 后切割 Rb。然而，尚不清楚切割对于 Rb 降解为什么是必需的。在这里，我们报告说蛋白酶体不能有效地在全长 Rb 上启动降解。钙蛋白酶切割暴露出被蛋白酶体识别的区域，导致 Rb 的快速蛋白水解。这些发现为通过控制起始来调节蛋白质稳定性的机制提供了依据，并为 HPV 转化的分子机制提供了更好的理解。
