Arnold Edward A, Smith Julian R, Leung Katie, Nguyen Daniel H, Kelnhofer-Millevolte Laurel E, Guo Monica S, Smith Jason G, Avgousti Daphne C
Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, USA.
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
J Virol. 2025 Feb 25;99(2):e0146224. doi: 10.1128/jvi.01462-24. Epub 2024 Dec 31.
Due to the importance of post-translational modification (PTM) in cellular function, viruses have evolved to both take advantage of and be susceptible to such modification. Adenovirus encodes a multifunctional protein called protein VII, which is packaged with the viral genome in the core of virions and disrupts host chromatin during infection. Protein VII has several PTMs whose addition contributes to the subnuclear localization of protein VII. Here, we used mutant viruses that abrogate or mimic these PTMs on protein VII to interrogate their impact on protein VII function during adenovirus infection. We discovered that acetylation of the lysine in positions 2 or 3 (K2 or K3) is deleterious during early infection as mutation to alanine led to greater intake of protein VII and viral DNA to the nucleus and enhanced early gene expression. Furthermore, we determined that protein VII is acetylated at alternative residues late during infection which may compensate for the mutated sites. Lastly, due to the role of the early viral protein E1A in viral gene activation, we investigated the interaction between protein VII and E1A and demonstrated that protein VII interacts with E1A through a chromatin-mediated interaction. Together, these results emphasize that the complexity of virus-host interactions is intimately tied to post-translational modification.
Adenoviruses are ubiquitous human pathogens that cause a variety of diseases, such as respiratory infections, gastroenteritis, and conjunctivitis. While often viewed as a self-limiting infection in healthy individuals, adenoviruses are particularly harmful to immunocompromised patients. Here, we investigate the functional role of post-translational modifications (PTMs) on an essential adenovirus core protein, protein VII, describing how they regulate its function during the early and late stages of infection. Our study focuses on how specific PTMs on protein VII influence transcription, localization, and interactions with other proteins, highlighting how PTMs are employed by viruses to alter protein function.
由于翻译后修饰（PTM）在细胞功能中具有重要性，病毒已经进化到既能利用这种修饰，又容易受到这种修饰的影响。腺病毒编码一种名为蛋白VII的多功能蛋白，该蛋白与病毒基因组一起包装在病毒粒子的核心中，并在感染期间破坏宿主染色质。蛋白VII有几种翻译后修饰，这些修饰的添加有助于蛋白VII的亚核定位。在这里，我们使用在蛋白VII上消除或模拟这些翻译后修饰的突变病毒，来探究它们在腺病毒感染期间对蛋白VII功能的影响。我们发现，在早期感染期间，第2或3位赖氨酸（K2或K3）的乙酰化是有害的，因为突变为丙氨酸会导致更多的蛋白VII和病毒DNA进入细胞核，并增强早期基因表达。此外，我们确定在感染后期，蛋白VII在其他残基处被乙酰化，这可能补偿了突变位点。最后，由于早期病毒蛋白E1A在病毒基因激活中的作用，我们研究了蛋白VII与E1A之间的相互作用，并证明蛋白VII通过染色质介导的相互作用与E1A相互作用。总之，这些结果强调病毒-宿主相互作用的复杂性与翻译后修饰密切相关。
腺病毒是普遍存在的人类病原体，可引起多种疾病，如呼吸道感染、肠胃炎和结膜炎。虽然在健康个体中通常被视为自限性感染，但腺病毒对免疫功能低下的患者特别有害。在这里，我们研究翻译后修饰（PTM）对腺病毒核心蛋白蛋白VII的功能作用，描述它们如何在感染的早期和晚期调节其功能。我们的研究重点是蛋白VII上的特定翻译后修饰如何影响转录、定位以及与其他蛋白的相互作用，突出了病毒如何利用翻译后修饰来改变蛋白功能。
