Abstract
The US3 serine/threonine protein kinase is conserved among the alphaherpesvirus family and represents an important virulence factor. US3 plays a role in viral nuclear egress, induces dramatic alterations of the cytoskeleton, represses apoptosis, enhances gene expression and modulates the immune response. Although several substrates of US3 have been identified, an unbiased screen to identify US3 phosphorylation targets has not yet been described. Here, we perform a shotgun and phosphoproteomics analysis of cells expressing the US3 protein of pseudorabies virus (PRV) to identify US3 phosphorylation targets in an unbiased way. We identified several cellular proteins that are differentially phosphorylated upon US3 expression and validated the phosphorylation of lamin A/C at serine 404, both in US3-transfected and PRV-infected cells. These results provide new insights into the signaling network of the US3 protein kinase and may serve as a basis for future research into the role of the US3 protein in the viral replication cycle.
Highlights
Herpesviruses are among the most successful pathogens worldwide, establishing lifelong latent infections in their natural host
Even though the transfection efficiencies were similar, the wild type, active version of pseudorabies virus (PRV) US3 showed higher expression compared to the inactive form of US3, which is in line with previous observations in our lab that kinase-active US3 appears to be more stable than its kinase negative version
We used a mass spectrometry approach to identify proteins differentially phosphorylated upon expression of the US3 protein versus approach to proteins US3 differentially phosphorylated upon78expression of the
Summary
Herpesviruses are among the most successful pathogens worldwide, establishing lifelong latent infections in their natural host. Their success correlates with the tight control that herpesviruses exert on different cellular pathways, sometimes by mimicking cellular proteins. One strategy to gain control over the host cell employed by herpesviruses is the expression of viral protein kinases that phosphorylate a wide range of both viral and cellular proteins [1,2]. All herpesviruses encode at least one protein kinase, while alphaherpesviruses encode two. The herpes simplex virus (HSV) and pseudorabies virus (PRV) homologues of the protein kinase conserved in all herpesviruses are called. The conserved alphaherpesvirus protein kinase homologues in HSV and PRV are called US3
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