Institute of Immunology and Microbiology, First Medical Faculty of Charles University, 12800 Prague, Czech Republic.
J Biol Chem. 2012 May 11;287(20):16199-208. doi: 10.1074/jbc.M111.335216. Epub 2012 Mar 27.
The Kaposi sarcoma-associated herpesvirus (KSHV) has been linked to Kaposi sarcoma, body cavity-based lymphoma, and Castleman disease. vIRF-3 is a KSHV latent gene that is critical for proliferation of KSHV-positive lymphoid cells. Furthermore, vIRF-3 contributes to KSHV-associated pathogenesis by stimulating c-Myc transcription activity. Here we show that vIRF-3 can associate with Skp2, a key component of the SCF(skp2) ubiquitin ligase complex. Skp2 is a transcriptional co-factor for c-Myc that was shown to regulate the stability of c-Myc protein as well as c-Myc-dependent transcription. In this study, we show that vIRF-3 binds to the F-box of Skp2 and recruits it to c-Myc-regulated promoters to activate c-Myc-dependent transcription. Additionally, cells overexpressing vIRF-3 exhibit higher levels of c-Myc ubiquitylation, suggesting that ubiquitylation is necessary for c-Myc-mediated transcription. Moreover, vIRF-3 can stabilize the c-Myc protein by increasing its half-life. Collectively, these results indicate that vIRF-3 can effectively manipulate c-Myc stability and function and thus contribute to c-Myc-induced KSHV-associated lymphomagenesis.
卡波济肉瘤相关疱疹病毒（KSHV）与卡波济肉瘤、体腔淋巴瘤和卡斯尔曼病有关。vIRF-3 是 KSHV 的潜伏基因，对 KSHV 阳性淋巴样细胞的增殖至关重要。此外，vIRF-3 通过刺激 c-Myc 转录活性，促进 KSHV 相关发病机制。在这里，我们表明 vIRF-3 可以与 Skp2 相关联，Skp2 是 SCF(skp2)泛素连接酶复合物的关键组成部分。Skp2 是 c-Myc 的转录共因子，已被证明可调节 c-Myc 蛋白的稳定性以及 c-Myc 依赖性转录。在这项研究中，我们表明 vIRF-3 与 Skp2 的 F -box 结合，并将其招募到 c-Myc 调节的启动子上，以激活 c-Myc 依赖性转录。此外，过表达 vIRF-3 的细胞表现出更高水平的 c-Myc 泛素化，表明泛素化对于 c-Myc 介导的转录是必要的。此外，vIRF-3 可以通过增加其半衰期来稳定 c-Myc 蛋白。总之，这些结果表明 vIRF-3 可以有效地操纵 c-Myc 的稳定性和功能，从而促进 c-Myc 诱导的 KSHV 相关淋巴瘤的发生。
