Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, Lebanon.
PLoS Pathog. 2021 Jan 20;17(1):e1009219. doi: 10.1371/journal.ppat.1009219. eCollection 2021 Jan.
Adult T cell leukemia (ATL) is an aggressive malignancy secondary to chronic infection by the human T-cell leukemia virus type 1 (HTLV-1) infection. Two viral proteins, Tax and HBZ, play central roles in ATL leukemogenesis. Tax expression transforms T cells in vitro and induces ATL-like disease in mice. Tax also induces a rough eye phenotype and increases hemocyte count in Drosophila melanogaster, indicative of transformation. Among multiple functions, Tax modulates the expression of the enhancer of zeste homolog 2 (EZH2), a methyltransferase of the Polycomb Repressive Complex 2 (PRC2), leading to H3K27me3-dependent reprogramming of around half of cellular genes. HBZ is a negative regulator of Tax-mediated viral transcription. HBZ effects on epigenetic signatures are underexplored. Here, we established an hbz transgenic fly model, and demonstrated that, unlike Tax, which induces NF-κB activation and enhanced PRC2 activity creating an activation loop, HBZ neither induces transformation nor NF-κB activation in vivo. However, overexpression of Tax or HBZ increases the PRC2 activity and both proteins directly interact with PRC2 complex core components. Importantly, overexpression of HBZ in tax transgenic flies prevents Tax-induced NF-κB or PRC2 activation and totally rescues Tax-induced transformation and senescence. Our results establish the in vivo antagonistic effect of HBZ on Tax-induced transformation and cellular effects. This study helps understanding long-term HTLV-1 persistence and cellular transformation and opens perspectives for new therapeutic strategies targeting the epigenetic machinery in ATL.
成人 T 细胞白血病 (ATL) 是由人类 T 细胞白血病病毒 1 (HTLV-1) 慢性感染引起的侵袭性恶性肿瘤。两种病毒蛋白，Tax 和 HBZ，在 ATL 白血病发生中发挥核心作用。Tax 在体外转化 T 细胞，并在小鼠中诱导 ATL 样疾病。Tax 还诱导果蝇粗糙眼表型和血细胞计数增加，表明发生转化。Tax 具有多种功能，可调节增强子结合锌指蛋白 2 同源物 (EZH2) 的表达，EZH2 是多梳抑制复合物 2 (PRC2) 的甲基转移酶，导致大约一半的细胞基因发生依赖 H3K27me3 的重编程。HBZ 是 Tax 介导的病毒转录的负调节剂。HBZ 对表观遗传特征的影响尚未得到充分探索。在这里，我们建立了 hbz 转基因果蝇模型，并证明与 Tax 不同，Tax 诱导 NF-κB 激活并增强 PRC2 活性，形成激活环，HBZ 既不会在体内诱导转化，也不会诱导 NF-κB 激活。然而，Tax 或 HBZ 的过表达会增加 PRC2 活性，并且这两种蛋白均可直接与 PRC2 复合物核心成分相互作用。重要的是，在 tax 转基因果蝇中过表达 HBZ 可阻止 Tax 诱导的 NF-κB 或 PRC2 激活，并完全挽救 Tax 诱导的转化和衰老。我们的结果确立了 HBZ 在体内对 Tax 诱导的转化和细胞效应的拮抗作用。这项研究有助于理解 HTLV-1 的长期持续存在和细胞转化，并为针对 ATL 中表观遗传机制的新治疗策略开辟了前景。
