Dataset Information

Viral retasking of hBre1/RNF20 to recruit hPaf1 for transcriptional activation.

ABSTRACT: Upon infection, human adenovirus (HAdV) must activate the expression of its early genes to reprogram the cellular environment to support virus replication. This activation is orchestrated in large part by the first HAdV gene expressed during infection, early region 1A (E1A). E1A binds and appropriates components of the cellular transcriptional machinery to modulate cellular gene transcription and activate viral early genes transcription. Previously, we identified hBre1/RNF20 as a target for E1A. The interaction between E1A and hBre1 antagonizes the innate antiviral response by blocking H2B monoubiquitination, a chromatin modification necessary for the interferon (IFN) response. Here, we describe a second distinct role for the interaction of E1A with hBre1 in transcriptional activation of HAdV early genes. Furthermore, we show that E1A changes the function of hBre1 from a ubiquitin ligase involved in substrate selection to a scaffold which recruits hPaf1 as a means to stimulate transcription and transcription-coupled histone modifications. By using hBre1 to recruit hPaf1, E1A is able to optimally activate viral early transcription and begin the cycle of viral replication. The ability of E1A to target hBre1 to simultaneously repress cellular IFN dependent transcription while activating viral transcription, represents an elegant example of the incredible economy of action accomplished by a viral regulatory protein through a single protein interaction.

SUBMITTER: Fonseca GJ

PROVIDER: S-EPMC3681745 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Viral retasking of hBre1/RNF20 to recruit hPaf1 for transcriptional activation.

Fonseca Gregory J GJ Cohen Michael J MJ Nichols Anthony C AC Barrett John W JW Mymryk Joe S JS

PLoS pathogens 20130613 6

Upon infection, human adenovirus (HAdV) must activate the expression of its early genes to reprogram the cellular environment to support virus replication. This activation is orchestrated in large part by the first HAdV gene expressed during infection, early region 1A (E1A). E1A binds and appropriates components of the cellular transcriptional machinery to modulate cellular gene transcription and activate viral early genes transcription. Previously, we identified hBre1/RNF20 as a target for E1A. ...[more]

PMID: 23785282

Similar Datasets

Project description:Viral engagement with macrophages activates Toll-Like-Receptors (TLRs) and viruses must contend with the ensuing inflammatory responses to successfully complete their replication cycle. To date, known counter-strategies involve the use of viral-encoded proteins that often employ mimicry mechanisms to block or redirect the host response to benefit the virus. Whether viral regulatory DNA sequences provide an opportunistic strategy by which viral enhancer elements functionally mimic innate immune enhancers is unknown. Here we find that host innate immune genes and the prototypical viral enhancer of cytomegalovirus (CMV) have comparable expression kinetics, and positively respond to common TLR agonists. In macrophages but not fibroblasts we show that activation of NF?B at immediate-early times of infection is independent of virion-associated protein, M45. We find upon virus infection or transfection of viral genomic DNA the TLR-agonist treatment results in significant enhancement of the virus transcription-replication cycle. In macrophage time-course infection experiments we demonstrate that TLR-agonist stimulation of the viral enhancer and replication cycle is strictly delimited by a temporal gate with a determined half-maximal time for enhancer-activation of 6 h; after which TLR-activation blocks the viral transcription-replication cycle. By performing a systematic siRNA screen of 149 innate immune regulatory factors we identify not only anticipated anti-viral and pro-viral contributions but also new factors involved in the CMV transcription-replication cycle. We identify a central convergent NF?B-SP1-RXR-IRF axis downstream of TLR-signalling. Activation of the RXR component potentiated direct and indirect TLR-induced activation of CMV transcription-replication cycle; whereas chromatin binding experiments using wild-type and enhancer-deletion virus revealed IRF3 and 5 as new pro-viral host transcription factor interactions with the CMV enhancer in macrophages. In a series of pharmacologic, siRNA and genetic loss-of-function experiments we determined that signalling mediated by the TLR-adaptor protein MyD88 plays a vital role for governing the inflammatory activation of the CMV enhancer in macrophages. Downstream TLR-regulated transcription factor binding motif disruption for NF?B, AP1 and CREB/ATF in the CMV enhancer demonstrated the requirement of these inflammatory signal-regulated elements in driving viral gene expression and growth in cells as well as in primary infection of neonatal mice. Thus, this study shows that the prototypical CMV enhancer, in a restricted time-gated manner, co-opts through DNA regulatory mimicry elements, innate-immune transcription factors to drive viral expression and replication in the face of on-going pro-inflammatory antiviral responses in vitro and in vivo and; suggests an unexpected role for inflammation in promoting acute infection and has important future implications for regulating latency.

Project description:: African swine fever is a devastating hemorrhagic infectious disease, which affects domestic and wild swines (Susscrofa) of all breeds and ages, with a high lethality of up to 90-100% in naïve animals. The causative agent, African swine fever virus (ASFV), is a large and complex double-stranded DNA arbovirus which is currently spreading worldwide, with serious socioeconomic consequences. There is no treatment or effective vaccine commercially available, and most of the current research is focused on attenuated viral models, with limited success so far. Thus, new strategies are under investigation. Extracellular vesicles (EVs) have proven to be a promising new vaccination platform for veterinary diseases in situations in which conventional approaches have not been completely successful. Here, serum extracellular vesicles from infected pigs using two different ASFV viruses (OURT 88/3 and Benin ΔMGF), corresponding to a naturally attenuated virus and a deletion mutant, respectively, were characterized in order to determine possible differences in the content of swine and viral proteins in EV-enriched fractions. Firstly, EVs were characterized by their CD5, CD63, CD81 and CD163 surface expression. Secondly, ASFV proteins were detected on the surface of EVs from ASFV-infected pig serum. Finally, proteomic analysis revealed few specific proteins from ASFV in the EVs, but 942 swine proteins were detected in all EV preparations (negative controls, and OURT 88/3 and Benin ΔMGF-infected preparations). However, in samples from OURT 88/3-infected animals, only a small number of proteins were differentially identified compared to control uninfected animals. Fifty-six swine proteins (Group Benin) and seven proteins (Group OURT 88/3) were differentially detected on EVs when compared to the EV control group. Most of these were related to coagulation cascades. The results presented here could contribute to a better understanding of ASFV pathogenesis and immune/protective responses in the host.

Dataset Information

Viral retasking of hBre1/RNF20 to recruit hPaf1 for transcriptional activation.

Publications

Viral retasking of hBre1/RNF20 to recruit hPaf1 for transcriptional activation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets