Abstract
To infect their hosts, DNA viruses must successfully initiate the expression of viral genes that control subsequent viral gene expression and manipulate the host environment. Viral genes that are immediately expressed upon infection play critical roles in the early infection process. In this study, we investigated the expression and regulation of five canonical regulatory immediate-early (IE) genes of Autographa californica multicapsid nucleopolyhedrovirus: ie0, ie1, ie2, me53, and pe38. A systematic transient gene-expression analysis revealed that these IE genes are generally transactivators, suggesting the existence of a highly interactive regulatory network. A genetic analysis using gene knockout viruses demonstrated that the expression of these IE genes was tolerant to the single deletions of activator IE genes in the early stage of infection. A network graph analysis on the regulatory relationships observed in the transient expression analysis suggested that the robustness of IE gene expression is due to the organization of the IE gene regulatory network and how each IE gene is activated. However, some regulatory relationships detected by the genetic analysis were contradictory to those observed in the transient expression analysis, especially for IE0-mediated regulation. Statistical modeling, combined with genetic analysis using knockout alleles for ie0 and ie1, showed that the repressor function of ie0 was due to the interaction between ie0 and ie1, not ie0 itself. Taken together, these systematic approaches provided insight into the topology and nature of the IE gene regulatory network.
Highlights
The initiation of signal transduction is one of the most important steps during any biological process, because it may determine how subsequent signaling events behave and the outcomes of the signaling process
A recombinant Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) with a mutated ie0 promoter reduced the expression of ie0 and increased steady-state levels of IE1 to higher than those of IE0 [20]. These findings indicate that the regulatory relationships between immediate early (IE) genes predicted by transient expression analyses may not necessarily correspond to those found during viral infections
The regulatory relationships observed in the systematic transient expression analysis were used to build a model for the AcMNPV IE gene regulatory network
Summary
The initiation of signal transduction is one of the most important steps during any biological process, because it may determine how subsequent signaling events behave and the outcomes of the signaling process. In contrast to the other four IE genes, the transcriptional regulatory function of me has yet to be determined; ME53 has a predicted zinc finger motif, which suggests a DNA sequence–specific binding function [8]. In addition to these IE genes, gp and p35 are expressed during the immediate early stage [3,22]. P35 does not contain any known domains with a transcriptional regulatory function, and the enhancement of late gene expression is mediated by stimulating replication of the DNA template for viral gene transcription [28]
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