Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Microbiology and Immunology

Supervisor

Dr. J.S. Mymryk

Abstract

Upon infection, human adenovirus (HAdV) must block interferon signaling and activate the expression of its early genes to reprogram the cellular environment to support virus replication. During the initial phase of infection, these processes are orchestrated 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. We have identified hBre1/RNF20 as a novel target of E1A. hBre1 is an E3 ubiquitin ligase which acts with the Ube2b E2 conjugase and accessory factors RNF40 and WAC1 to monoubiquitinate H2B at K120 (H2B-ub), a mark of chromatin which is highly transcriptionally active. hBre1 and the activity of the hBre1 complex to monoubiquitinate H2B, was found to be critical for interferon mediated induction of interferon stimulated genes (ISGs) and the establishment of an anti-viral state. During infection, E1A targets hBre1 at ISG gene bodies and blocks the catalytic component of the hBre1 complex, Ube2b from being recruited to ISGs. As a result, E1A can antagonize the innate antiviral response by blocking H2B monoubiquitination and, as such, ISG transcription. In contrast to blocking hBre1 activity at ISGs, E1A is able to recruit hBre1 to viral chromatin where hBre1 participates in the transactivation of HAdV early genes. As E1A blocks the catalytic activity of the hBre1 complex, E1A retasks hBre1, altering hBre1 function from an E3 conjugase to a scaffold which recruits the cellular transactivator, hPaf1. hPaf1 is recruited by hBre1 and E1A to HAdV early genes to induce activating histone posttranslational modifications, H3K4 trimethylation and H3K79 trimethylation. 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.

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