Dataset Information

Fos Facilitates Gallid Alpha-Herpesvirus 1 Infection by Transcriptional Control of Host Metabolic Genes and Viral Immediate Early Gene.

ABSTRACT: Gallid alpha-herpesvirus 1, also known as avian infectious laryngotracheitis virus (ILTV), continues to cause huge economic losses to the poultry industry worldwide. Similar to that of other herpesvirus-encoded proteins, the expression of viral genes encoded by ILTV is regulated by a cascade, and the underlying regulatory mechanism remains largely unclear. The viral immediate-early (IE) gene ICP4 plays a prominent role in the initiation of the transcription of early and late genes during ILTV replication. In this study, we identified AP-1 as the key regulator of the transcription of ILTV genes by bioinformatics analysis of genome-wide transcriptome data. Subsequent functional studies of the key members of the AP-1 family revealed that Fos, but not Jun, regulates ILTV infection through AP-1 since knockdown of Fos, but not Jun, by gene silencing significantly reduced ICP4 transcription and subsequent viral genome replication and virion production. Using several approaches, we identified ICP4 as a bona fide target gene of Fos that regulated Fos and has Fos response elements within its promoter. Neither the physical binding of Jun to the promoter of ICP4 nor the transcriptional activity of Jun was observed. In addition, knockdown of Fos reduced the transcription of MDH1 and ATP5A1, genes encoding two host rate-limiting enzymes essential for the production of the TCA intermediates OAA and ATP. The biological significance of the transcriptional regulation of MDH1 and ATP5A1 by Fos in ILTV infection was supported by the fact that anaplerosis of OAA and ATP rescued both ICP4 transcription and virion production in infected cells under when Fos was silenced. Our study identified the transcription factor Fos as a key regulator of ILTV infection through its transcription factor function on both the virus and host sides, improving the current understanding of both avian herpesvirus-host interactions and the roles of AP-1 in viral infection.

SUBMITTER: Wang Z

PROVIDER: S-EPMC8229045 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Although it is widely accepted that herpesviruses utilize host RNA polymerase II (RNAPII) to transcribe viral genes, the mechanism of utilization varies significantly among herpesviruses. With the exception of herpes simplex virus 1 (HSV-1) in alpha-herpesviruses, the mechanism by which RNAPII transcribes viral genes in the remaining alpha-herpesviruses has not been reported. In this study, we investigated the transcriptional mechanism of an avian alpha-herpesvirus, Anatid herpesvirus 1 (AnHV-1). We discovered for the first time that hexamethylene-bis-acetamide-inducing protein 1 (HEXIM1), a major inhibitor of positive elongation factor B (P-TEFb), was significantly upregulated during AnHV-1 infection, and its expression was dynamically regulated throughout the progression of the disease. However, the expression level of HEXIM1 remained stable before and after HSV-1 infection. Excessive HEXIM1 assists AnHV-1 in progeny virus production, gene expression, and RNA polymerase II recruitment by promoting the formation of more inactive P-TEFb and the loss of RNAPII S2 phosphorylation. Conversely, the expression of some host survival-related genes, such as SOX8, CDK1, MYC, and ID2, was suppressed by HEXIM1 overexpression. Further investigation revealed that the C-terminus of the AnHV-1 US1 gene is responsible for the upregulation of HEXIM1 by activating its promoter but not by interacting with P-TEFb, which is the mechanism adopted by its homologs, HSV-1 ICP22. Additionally, the virus proliferation deficiency caused by US1 deletion during the early infection stage could be partially rescued by HEXIM1 overexpression, suggesting that HEXIM1 is responsible for AnHV-1 gaining transcription advantages when competing with cells. Taken together, this study revealed a novel HEXIM1-dependent AnHV-1 transcription mechanism, which has not been previously reported in herpesvirus or even DNA virus studies.IMPORTANCEHexamethylene-bis-acetamide-inducing protein 1 (HEXIM1) has been identified as an inhibitor of positive transcriptional elongation factor b associated with cancer, AIDS, myocardial hypertrophy, and inflammation. Surprisingly, no previous reports have explored the role of HEXIM1 in herpesvirus transcription. This study reveals a mechanism distinct from the currently known herpesvirus utilization of RNA polymerase II, highlighting the dependence on high HEXIM1 expression, which may be a previously unrecognized facet of the host shutoff manifested by many DNA viruses. Moreover, this discovery expands the significance of HEXIM1 in pathogen infection. It raises intriguing questions about whether other herpesviruses employ similar mechanisms to manipulate HEXIM1 and if this molecular target can be exploited to limit productive replication. Thus, this discovery not only contributes to our understanding of herpesvirus infection regulation but also holds implications for broader research on other herpesviruses, even DNA viruses.

Project description:Apoptosis is a common innate defense mechanism of host cells against viral infection and is therefore suppressed by many viruses, including herpes simplex virus (HSV), via various strategies. A recent in vivo study reported the apoptosis of remote uninfected cells during Gallid herpesvirus 1 (GaHV-1) infection, yet little is known about this previously unknown aspect of herpesvirus-host interactions. The aim of the present study was to investigate the apoptosis of uninfected host cells during GaHV-1 infection. The present study used in vitro and in ovo models, which avoided potential interference by host antiviral immunity, and demonstrated that this GaHV-1-host interaction is independent of host immune responses and important for both the pathological effect of viral infection and early viral dissemination from the primary infection site to distant tissues. Further, we revealed that GaHV-1 infection triggers this process in a paracrine-regulated manner. Using genome-wide transcriptome analyses in combination with a set of functional studies, we found that this paracrine-regulated effect requires the repression of p53 activity in uninfected cells. In contrast, the activation of p53 not only prevented the apoptosis of remote uninfected cells and subsequent pathological damage induced by GaHV-1 infection but also delayed viral dissemination significantly. Moreover, p53 activation repressed viral replication both in vitro and in ovo, suggesting that dual cell-intrinsic mechanisms underlie the suppression of GaHV-1 infection by p53 activation. This study uncovers the mechanism underlying the herpesvirus-triggered apoptosis of remote host cells and extends our understanding of both herpesvirus-host interactions and the roles of p53 in viral infection.IMPORTANCE It is well accepted that herpesviruses suppress the apoptosis of host cells via various strategies to ensure sustained viral replication during infection. However, a recent in vivo study reported the apoptosis of remote uninfected cells during GaHV-1 infection. The mechanism and the biological meaning of this unexpected herpesvirus-host interaction are unclear. This study uncovers the mechanisms of herpesvirus-triggered apoptosis in uninfected cells and may also contribute to a mechanistic illustration of paracrine-regulated apoptosis induced by other viruses in uninfected host cells.

Dataset Information

Fos Facilitates Gallid Alpha-Herpesvirus 1 Infection by Transcriptional Control of Host Metabolic Genes and Viral Immediate Early Gene.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets