Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.
J Virol. 2024 Jul 23;98(7):e0040524. doi: 10.1128/jvi.00405-24. Epub 2024 Jun 14.
Human T-cell leukemia virus type 1 (HTLV-I) is the etiological agent of adult T-cell leukemia (ATL). Mutational analysis has demonstrated that the tumor suppressor, F-box and WD repeat domain containing 7 (FBXW7/FBW7/CDC4), is mutated in primary ATL patients. However, even in the absence of genetic mutations, FBXW7 substrates are stabilized in ATL cells, suggesting additional mechanisms can prevent FBXW7 functions. Here, we report that the viral oncoprotein Tax represses FBXW7 activity, resulting in the stabilization of activated Notch intracellular domain, c-MYC, Cyclin E, and myeloid cell leukemia sequence 1 (BCL2-related) (Mcl-1). Mechanistically, we demonstrate that Tax directly binds to FBXW7 in the nucleus, effectively outcompeting other targets for binding to FBXW7, resulting in decreased ubiquitination and degradation of FBXW7 substrates. In support of the nuclear role of Tax, a non-degradable form of the nuclear factor kappa B subunit 2 (NFκB2/p100) was found to delocalize Tax to the cytoplasm, thereby preventing Tax interactions with FBXW7 and Tax-mediated inhibition of FBXW7. Finally, we characterize a Tax mutant that is unable to interact with FBXW7, unable to block FBXW7 tumor suppressor functions, and unable to effectively transform fibroblasts. These results demonstrate that HTLV-I Tax can inhibit FBXW7 functions without genetic mutations to promote an oncogenic state. These results suggest that Tax-mediated inhibition of FBXW7 is likely critical during the early stages of the cellular transformation process.
F-box and WD repeat domain containing 7 (FBXW7), a critical tumor suppressor of human cancers, is frequently mutated or epigenetically suppressed. Loss of FBXW7 functions is associated with stabilization and increased expression of oncogenic factors such as Cyclin E, c-Myc, Mcl-1, mTOR, Jun, and Notch. In this study, we demonstrate that the human retrovirus human T-cell leukemia virus type 1 oncoprotein Tax directly interacts with FBXW7, effectively outcompeting other targets for binding to FBXW7, resulting in decreased ubiquitination and degradation of FBXW7 cellular substrates. We further demonstrate that a Tax mutant unable to interact with and inactivate FBXW7 loses its ability to transform primary fibroblasts. Collectively, our results describe a novel mechanism used by a human tumor virus to promote cellular transformation.
人类 T 细胞白血病病毒 1（HTLV-I）是成人 T 细胞白血病（ATL）的病因。突变分析表明，肿瘤抑制因子 F 框和 WD 重复域包含 7（FBXW7/FBW7/CDC4）在原发性 ATL 患者中发生突变。然而，即使没有遗传突变，ATL 细胞中的 FBXW7 底物也会稳定，这表明存在其他机制可以防止 FBXW7 发挥功能。在这里，我们报告病毒癌蛋白 Tax 抑制 FBXW7 活性，导致激活的 Notch 细胞内结构域、c-MYC、细胞周期蛋白 E 和髓细胞白血病序列 1（BCL2 相关）（Mcl-1）的稳定。从机制上讲，我们证明 Tax 直接在核内与 FBXW7 结合，有效地与其他与 FBXW7 结合的靶标竞争，导致 FBXW7 底物的泛素化和降解减少。为了支持 Tax 的核作用，发现核因子 kappa B 亚单位 2（NFκB2/p100）的一种不可降解形式将 Tax 易位到细胞质中，从而阻止 Tax 与 FBXW7 的相互作用和 Tax 介导的 FBXW7 抑制。最后，我们对一种不能与 FBXW7 相互作用、不能阻断 FBXW7 肿瘤抑制功能、不能有效转化成纤维细胞的 Tax 突变体进行了表征。这些结果表明，HTLV-I Tax 可以在没有基因突变的情况下抑制 FBXW7 功能，从而促进致癌状态。这些结果表明，Tax 介导的 FBXW7 抑制在细胞转化过程的早期阶段可能至关重要。
F 框和 WD 重复域包含 7（FBXW7）是人类癌症的关键肿瘤抑制因子，经常发生突变或表观遗传抑制。FBXW7 功能的丧失与致癌因子如细胞周期蛋白 E、c-MYC、Mcl-1、mTOR、Jun 和 Notch 的稳定和表达增加有关。在这项研究中，我们证明人类逆转录病毒人类 T 细胞白血病病毒 1 癌蛋白 Tax 直接与 FBXW7 相互作用，有效地与其他与 FBXW7 结合的靶标竞争，导致 FBXW7 细胞底物的泛素化和降解减少。我们进一步证明，一种不能与 FBXW7 相互作用和失活的 Tax 突变体丧失了转化原代成纤维细胞的能力。总之，我们的研究结果描述了一种人类肿瘤病毒促进细胞转化所使用的新机制。
