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Herpes Simplex Virus Type 2 Immediate Early Protein ICP27 Inhibits IFN-? Production in Mucosal Epithelial Cells by Antagonizing IRF3 Activation.

ABSTRACT: Herpes simplex virus type 2 (HSV-2) is the main cause of genital herpes and infections are common in the lower genital tract. Although neuronal and immune cells can be infected, epithelial cells, and keratinocytes are the primary HSV-2 target cells. HSV-2 establishes latency by evading the host immune system and its infection can also increase the risk of HIV-1 sexual transmission. Our pervious study found that HSV-2 immediate early protein ICP22, inhibited IFN-? production by interfering with the IRF3 pathway. However, ICP22-null HSV-2 did not completely lose the capability of suppressing IFN-? induction, suggesting the involvement of other viral components in the process. In this study, by using an ex vivo cervical explant model, we first demonstrated that HSV-2 can indeed inhibit IFN-? induction in human mucosal tissues. We further identified HSV-2 immediate early protein ICP27 as a potent IFN-? antagonist. ICP27 significantly suppresses the Sendai virus or polyinosinic-polycytidylic acid-induced IFN-? production in human mucosal epithelial cells, showing that ICP27 inhibits the IFN-? promoter activation, and IFN-? production at both mRNA and protein levels. Additional studies revealed that ICP27 directly associates with IRF3 and inhibits its phosphorylation and nuclear translocation, resulting in the inhibition of IFN-? induction. Our findings provide insights into the molecular mechanism underlying HSV-2 mucosal immune evasion, and information for the design of HSV-2 mucosal vaccines.

SUBMITTER: Guan X

PROVIDER: S-EPMC6399465 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Herpes Simplex Virus Type 2 Immediate Early Protein ICP27 Inhibits IFN-β Production in Mucosal Epithelial Cells by Antagonizing IRF3 Activation.

Guan Xinmeng X Zhang Mudan M Fu Ming M Luo Sukun S Hu Qinxue Q

Frontiers in immunology 20190226

Herpes simplex virus type 2 (HSV-2) is the main cause of genital herpes and infections are common in the lower genital tract. Although neuronal and immune cells can be infected, epithelial cells, and keratinocytes are the primary HSV-2 target cells. HSV-2 establishes latency by evading the host immune system and its infection can also increase the risk of HIV-1 sexual transmission. Our pervious study found that HSV-2 immediate early protein ICP22, inhibited IFN-β production by interfering with t ...[more]

PMID: 30863402

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Project description:UnlabelledHerpesviruses are nuclear-replicating viruses that have successfully evolved to evade the immune system of humans, establishing lifelong infections. ICP27 from herpes simplex virus is a multifunctional regulatory protein that is functionally conserved in all known human herpesviruses. It has the potential to interact with an array of cellular proteins, as well as intronless viral RNAs. ICP27 plays an essential role in viral transcription, nuclear export of intronless RNAs, translation of viral transcripts, and virion host shutoff function. It has also been implicated in several signaling pathways and the prevention of apoptosis. Although much is known about its central role in viral replication and infection, very little is known about the structure and mechanistic properties of ICP27 and its homologs. We present the first crystal structure of ICP27 C-terminal domain at a resolution of 2.0 Å. The structure reveals the C-terminal half of ICP27 to have a novel fold consisting of α-helices and long loops, along with a unique CHCC-type of zinc-binding motif. The two termini of this domain extend from the central core and hint to possibilities of making interactions. ICP27 essential domain is capable of forming self-dimers as seen in the structure, which is confirmed by analytical ultracentrifugation study. Preliminary in vitro phosphorylation assays reveal that this domain may be regulated by cellular kinases.ImportanceICP27 is a key regulatory protein of the herpes simplex virus and has functional homologs in all known human herpesviruses. Understanding the structure of this protein is a step ahead in deciphering the mechanism by which the virus thrives. In this study, we present the first structure of the C-terminal domain of ICP27 and describe its novel features. We critically analyze the structure and compare our results to the information available form earlier studies. This structure can act as a guide in future experimental designs and can add to a better understanding of mechanism of ICP27, as well as that of its homologs.

Dataset Information

Herpes Simplex Virus Type 2 Immediate Early Protein ICP27 Inhibits IFN-? Production in Mucosal Epithelial Cells by Antagonizing IRF3 Activation.

Publications

Herpes Simplex Virus Type 2 Immediate Early Protein ICP27 Inhibits IFN-β Production in Mucosal Epithelial Cells by Antagonizing IRF3 Activation.

Similar Datasets

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