Viral infections are associated with extensive remodeling of the cellular
proteome. Viruses encode gene products that manipulate host
proteins to redirect cellular processes or subvert
antiviral immune responses. Adenovirus (AdV) encodes
proteins from the early E4 region which are necessary for productive
infection. Some cellular
antiviral proteins are known to be targeted by AdV E4 gene products, resulting in their degradation or mislocalization. However, the full repertoire of host
proteome changes induced by viral E4
proteins has not been defined. To identify cellular
proteins and processes manipulated by viral products, we developed a global, unbiased proteomics approach to analyze changes to the host
proteome during
infection with adenovirus serotype 5 (Ad5) virus. We used whole-cell proteomics to measure total
protein abundances in the
proteome during Ad5
infection. Since host
antiviral proteins can antagonize
viral infection by associating with viral genomes and inhibiting essential viral processes, we used Isolation of
Proteins on Nascent
DNA (iPOND) proteomics to identify
proteins associated with viral genomes during
infection with wild-type Ad5 or an E4 mutant virus. By integrating these proteomics data sets, we identified cellular factors that are degraded in an E4-dependent manner or are associated with the viral genome in the absence of E4
proteins. We further show that some identified
proteins exert inhibitory effects on Ad5
infection. Our systems-level analysis reveals cellular processes that are manipulated during Ad5
infection and points to host factors counteracted by early
viral proteins as they remodel the host
proteome to promote efficient
infection. IMPORTANCE
Viral infections induce myriad changes to the host cell
proteome. As viruses harness cellular processes and counteract host defenses, they impact abundance, post-translational modifications, interactions, or localization of cellular
proteins. Elucidating the dynamic changes to the cellular
proteome during viral replication is integral to understanding how virus-host interactions influence the outcome of
infection. Adenovirus encodes early gene products from the E4 genomic region that are known to alter host response pathways and promote replication, but the full extent of
proteome modifications they mediate is not known. We used an integrated proteomics approach to quantitate
protein abundance and
protein associations with
viral DNA during
virus infection. Systems-level analysis identifies cellular
proteins and processes impacted in an E4-dependent manner, suggesting ways that adenovirus counteracts potentially inhibitory host defenses. This study provides a global view of adenovirus-mediated
proteome remodeling, which can serve as a model to investigate virus-host interactions of DNA viruses.