Post-translational modifications on protein VII are important during the early stages of adenovirus infection.

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. IMPORTANCE: 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.