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Abstract
The oncoproteins of the small DNA tumor viruses interact with a plethora of cellular regulators to commandeer control of the infected cell. During infection, adenovirus E1A deregulates cAMP signalling and repurposes it for activation of viral gene expression. We show that E1A structurally and functionally mimics a cellular A-kinase anchoring protein (AKAP). E1A interacts with and relocalizes protein kinase A (PKA) to the nucleus, likely to virus replication centres, via an interaction with the regulatory subunits of PKA. Binding to PKA requires the N-terminus of E1A, which bears striking similarity to the amphipathic α-helical domain present in cellular AKAPs. E1A also targets the same docking-dimerization domain of PKA normally bound by cellular AKAPs. In addition, the AKAP like motif within E1A could restore PKA interaction to a cellular AKAP in which its normal interaction motif was deleted. During infection, E1A successfully competes with endogenous cellular AKAPs for PKA interaction. E1A’s role as a viral AKAP contributes to viral transcription, protein expression and progeny production. These data establish HAdV E1A as the first known viral AKAP. This represents a unique example of viral subversion of a crucial cellular regulatory pathway via structural mimicry of the PKA interaction domain of cellular AKAPs.
Highlights
As obligate intracellular parasites, all viruses are critically dependent upon the host cell
The multifunctional E1A proteins of human adenovirus (HAdV) are adept at targeting key cellular regulators
We found that the protein kinase A (PKA) regulatory subunits are conserved targets of most HAdV E1A species
Summary
All viruses are critically dependent upon the host cell. Viral regulatory proteins have been relentlessly forged into exquisitely sophisticated instruments that functionally reprogram the infected cell [1]. Studies of human adenovirus (HAdV), a small DNA tumor virus, illustrate the profound impact of viral proteins on multiple host functions to maximize viral propagation [2,3,4,5,6,7]. The multifunctional E1A proteins of HAdV are adept at targeting key cellular regulators. Through these interactions, E1A creates a cellular milieu more conducive for replication. Many of the interaction motifs in E1A are functional mimics of highly similar sequences present in cellular regulatory proteins. Viral evolution has converged to generate specific high affinity protein interaction surfaces that perturb cell regulation by competing with endogenous targets
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