Herpesvirus proteins that target key cellular processes
Herpes simplex virus, Epstein–Barr virus, and cytomegalovirus are three types of human herpesviruses that infect most people for their entire life and, under some circumstances, cause significant diseases. Each virus encodes a large number of proteins that function to manipulate the host cell to the best advantage of the virus. However, many of these encoded proteins have never been studied. A new study suggests that herpesviruses use multiple strategies to manipulate important components of the host cell nuclear environment during infection, and provides novel insights into the potential functions of over 120 previously uncharacterized viral proteins.
Herpesviruses have complex life cycles due to their adept manipulation of the host cell environment. Although often asymptomatic, herpesviruses can cause life-threatening diseases. In order to provide a more complete understanding of how these viruses alter host cells, the researchers developed a system to examine each viral protein individually in human cells and investigated over 230 individual proteins from these three herpesviruses. They focused in detail on 93 identified virus proteins that localized to the cell nucleus and altered key cellular components that regulate gene expression, cell growth and death, and antiviral responses.
Cells depend on nuclear structures called PML bodies to control cell proliferation and survival, to ensure damaged DNA is repaired and to inhibit virus replication. 24 of the nuclear viral proteins, several of which had no previously assigned function, were found to disrupt or reorganize promyelocytic leukemia (PML) bodies, which are part of the cellular response to suppress viral replication, suggesting that herpesviruses employ multiple strategies for manipulating this key regulator of essential cellular processes. This study has given the first information on the potential function of 120 previously unstudied herpesvirus proteins and shows that each virus has multiple mechanisms to disrupt PML bodies that were not previously recognized. Further studies will be needed to determine how the identified virus proteins function in the context of virus infection, but this research provides a starting point for investigating how these proteins affect important processes of the cell nucleus.
Genome-Wide Screen of Three Herpesviruses for Protein Subcellular Localization and Alteration of PML Nuclear Bodies. PLoS Pathog 4(7): e1000100
Herpesviruses are large, ubiquitous DNA viruses with complex host interactions, yet many of the proteins encoded by these viruses have not been functionally characterized. As a first step in functional characterization, we determined the subcellular localization of 234 epitope-tagged proteins from herpes simplex virus, cytomegalovirus, and Epstein–Barr virus. Twenty-four of the 93 proteins with nuclear localization formed subnuclear structures. Twelve of these localized to the nucleolus, and five at least partially localized with promyelocytic leukemia (PML) bodies, which are known to suppress viral lytic infection. In addition, two proteins disrupted Cajal bodies, and 19 of the nuclear proteins significantly decreased the number of PML bodies per cell, including six that were shown to be SUMO-modified. These results have provided the first functional insights into over 120 previously unstudied proteins and suggest that herpesviruses employ multiple strategies for manipulating nuclear bodies that control key cellular processes.
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