Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras 2780-157, Portugal.
Nucleic Acids Res. 2021 Dec 16;49(22):12895-12911. doi: 10.1093/nar/gkab1094.
Mixed lineage leukemia 1 (MLL1) is a histone methyltransferase. Kaposi's sarcoma-associated herpesvirus (KSHV) is a leading cause of malignancy in AIDS. KSHV latently infects tumor cells and its genome is decorated with epigenetic marks. Here, we show that KSHV latency-associated nuclear antigen (LANA) recruits MLL1 to viral DNA where it establishes H3K4me3 modifications at the extensive KSHV terminal repeat elements during primary infection. LANA interacts with MLL1 complex members, including WDR5, integrates into the MLL1 complex, and regulates MLL1 activity. We describe the 1.5-Å crystal structure of N-terminal LANA peptide complexed with MLL1 complex member WDR5, which reveals a potential regulatory mechanism. Disruption of MLL1 expression rendered KSHV latency establishment highly deficient. This deficiency was rescued by MLL1 but not by catalytically inactive MLL1. Therefore, MLL1 is LANA regulable and exerts a central role in virus infection. These results suggest broad potential for MLL1 regulation, including by non-host factors.
混合谱系白血病 1（MLL1）是一种组蛋白甲基转移酶。卡波济肉瘤相关疱疹病毒（KSHV）是艾滋病导致恶性肿瘤的主要原因。KSHV 潜伏感染肿瘤细胞，其基因组被表观遗传标记修饰。在这里，我们表明 KSHV 潜伏相关核抗原（LANA）将 MLL1 招募到病毒 DNA 上，在原发性感染期间，在广泛的 KSHV 末端重复元件上建立 H3K4me3 修饰。LANA 与 MLL1 复合物成员相互作用，包括 WDR5，整合到 MLL1 复合物中，并调节 MLL1 活性。我们描述了与 MLL1 复合物成员 WDR5 结合的 N 端 LANA 肽的 1.5Å 晶体结构，揭示了一种潜在的调节机制。破坏 MLL1 的表达使 KSHV 潜伏建立高度不足。这种缺陷可以通过 MLL1 挽救，但不能通过无催化活性的 MLL1 挽救。因此，MLL1 受 LANA 调控，并在病毒感染中发挥核心作用。这些结果表明 MLL1 调节具有广泛的潜力，包括受非宿主因素调节。
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