Department of Cell and Molecular Biology, Karolinska Institutet, Box 285, S-17177 Stockholm, Sweden.
Nat Cell Biol. 2010 Apr;12(4):351-61. doi: 10.1038/ncb2035. Epub 2010 Feb 28.
The large tegument proteins of herpesviruses encode conserved cysteine proteases of unknown function. Here we show that BPLF1, the Epstein-Barr-virus-encoded member of this protease family, is a deneddylase that regulates virus production by modulating the activity of cullin-RING ligases (CRLs). BPLF1 hydrolyses NEDD8 conjugates in vitro, acts as a deneddylase in vivo, binds to cullins and stabilizes CRL substrates. Expression of BPLF1 alone or in the context of the productive virus cycle induces accumulation of the licensing factor CDT1 and deregulates S-phase DNA synthesis. Inhibition of BPLF1 during the productive virus cycle prevents cellular DNA re-replication and inhibits virus replication. Viral DNA synthesis is restored by overexpression of CDT1. Homologues encoded by other herpesviruses share the deneddylase activity. Thus, these enzymes are likely to have a key function in the virus life cycle by inducing a replication-permissive S-phase-like cellular environment.
疱疹病毒的大型被膜蛋白编码功能未知的保守半胱氨酸蛋白酶。在这里，我们表明，Epstein-Barr 病毒编码的该蛋白酶家族成员 BPLF1 是一种去连接酶，通过调节细胞周期蛋白-RING 连接酶 (CRL) 的活性来调节病毒产生。BPLF1 在体外水解 NEDD8 缀合物，在体内充当去连接酶，与细胞周期蛋白结合并稳定 CRL 底物。单独表达 BPLF1 或在有性病毒周期的背景下表达会诱导许可因子 CDT1 的积累，并使 S 期 DNA 合成失调。在有性病毒周期中抑制 BPLF1 可防止细胞 DNA 再复制并抑制病毒复制。通过过表达 CDT1 可恢复病毒 DNA 合成。其他疱疹病毒编码的同源物具有去连接酶活性。因此，这些酶可能通过诱导复制许可的 S 期样细胞环境在病毒生命周期中发挥关键作用。
