Abstract
Upon infection, human adenovirus (HAdV) must activate the expression of its early genes to reprogram the cellular environment to support virus replication. This activation is orchestrated in large part by the first HAdV gene expressed during infection, early region 1A (E1A). E1A binds and appropriates components of the cellular transcriptional machinery to modulate cellular gene transcription and activate viral early genes transcription. Previously, we identified hBre1/RNF20 as a target for E1A. The interaction between E1A and hBre1 antagonizes the innate antiviral response by blocking H2B monoubiquitination, a chromatin modification necessary for the interferon (IFN) response. Here, we describe a second distinct role for the interaction of E1A with hBre1 in transcriptional activation of HAdV early genes. Furthermore, we show that E1A changes the function of hBre1 from a ubiquitin ligase involved in substrate selection to a scaffold which recruits hPaf1 as a means to stimulate transcription and transcription-coupled histone modifications. By using hBre1 to recruit hPaf1, E1A is able to optimally activate viral early transcription and begin the cycle of viral replication. The ability of E1A to target hBre1 to simultaneously repress cellular IFN dependent transcription while activating viral transcription, represents an elegant example of the incredible economy of action accomplished by a viral regulatory protein through a single protein interaction.
Highlights
Viruses are obligate intracellular pathogens as they require cellular machinery to replicate
There exists a large body of research focusing on the role that conserved region 3 (CR3) plays in virus transcription, the requirement for the N-terminus, which is conserved in both the 289R and 243R early region 1A (E1A) proteins, and the mechanisms through which it cooperates with CR3 to activate viral transcription, are poorly understood
Adenovirus reprograms the infected cell using the early gene products. The transcription of these viral proteins is activated by the product of the first viral gene produced during adenoviral infection, early region 1A (E1A)
Summary
Viruses are obligate intracellular pathogens as they require cellular machinery to replicate. Human adenovirus (HAdV) is no exception, and during infection must appropriate the host cellular transcriptional apparatus to begin transcription of the viral genes necessary to reprogram the cellular environment [1,2]. This is done in large part by the viral products of Early Region 1A (E1A), the first gene transcribed after infection. The 289R and 243R E1A proteins of HAdV 5 are identical except for the presence of an additional 46 amino acid sequence within the 289R [5] This unique 46 amino acid region encompasses CR3 [6]. There exists a large body of research focusing on the role that CR3 plays in virus transcription, the requirement for the N-terminus, which is conserved in both the 289R and 243R E1A proteins, and the mechanisms through which it cooperates with CR3 to activate viral transcription, are poorly understood
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