The Papillomavirus E2 proteins

McBride, Alison A.

doi:10.1016/j.virol.2013.06.006

Cited by 349 publications

(421 citation statements)

References 285 publications

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“…Differentiation of infected epithelial cells leads to activation of early and then late gene expression (4). The viral replication and transcription factor, E2, is expressed at greatest levels in the middle to upper layers of the epithelium (5,6) where, together with the viral DNA helicase, E1, it facilitates vegetative viral DNA replication, leading to production of thousands of viral genome copies (7). The viral late proteins, including the capsid proteins L1 and L2, are synthesized in the uppermost granular layer of the epithelium to encapsidate the newly replicated genomes (4).…”

mentioning

confidence: 99%

Human Papillomavirus E2 Regulates SRSF3 (SRp20) To Promote Capsid Protein Expression in Infected Differentiated Keratinocytes

Klymenko

Hernandez-Lopez

MacDonald

et al. 2016

J Virol

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The human papillomavirus (HPV) life cycle is tightly linked to differentiation of the infected epithelial cell, suggesting a sophisticated interplay between host cell metabolism and virus replication. Previously, we demonstrated in differentiated keratinocytes in vitro and in vivo that HPV type 16 (HPV16) infection caused increased levels of the cellular SR splicing factors (SRSFs) SRSF1 (ASF/SF2), SRSF2 (SC35), and SRSF3 (SRp20). Moreover, the viral E2 transcription and replication factor that is expressed at high levels in differentiating keratinocytes could bind and control activity of the SRSF1 gene promoter. Here, we show that the E2 proteins of HPV16 and HPV31 control the expression of SRSFs 1, 2, and 3 in a differentiation-dependent manner. E2 has the greatest transactivation effect on expression of SRSF3. Small interfering RNA depletion experiments in two different models of the HPV16 life cycle (W12E and NIKS16) and one model of the HPV31 life cycle (CIN612-9E) revealed that only SRSF3 contributed significantly to regulation of late events in the virus life cycle. Increased levels of SRSF3 are required for L1 mRNA and capsid protein expression. Capsid protein expression was regulated specifically by SRSF3 and appeared independent of other SRSFs. Taken together, these data suggest a significant role of the HPV E2 protein in regulating late events in the HPV life cycle through transcriptional regulation of SRSF3 expression. IMPORTANCEHuman papillomavirus replication is accomplished in concert with differentiation of the infected epithelium. Virus capsid protein expression is confined to the upper epithelial layers so as to avoid immune detection. In this study, we demonstrate that the viral E2 transcription factor activates the promoter of the cellular SRSF3 RNA processing factor. SRSF3 is required for expression of the E4^L1 mRNA and so controls expression of the HPV L1 capsid protein. Thus, we reveal a new dimension of virus-host interaction crucial for production of infectious virus. SRSF proteins are known drug targets. Therefore, this study provides an excellent basis for developing strategies to regulate capsid protein production in the infected epithelium and the production of new virions.

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confidence: 99%

Human Papillomavirus E2 Regulates SRSF3 (SRp20) To Promote Capsid Protein Expression in Infected Differentiated Keratinocytes

Klymenko

Hernandez-Lopez

MacDonald

et al. 2016

J Virol

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“…These proteins include E1, which, in cooperation with E2, binds and licenses the ori for DNA replication by forming a hexameric helicase to unwind viral DNA and initiate the loading of host cell replication factors (2). E2 is a protein with multiple functions that include transcriptional repression of the viral oncogenes E6 and E7 (3). E6 and E7 are required for maintenance of the viral genome, including assisting unscheduled rounds of DNA synthesis in differentiating keratinocytes in support of the productive phase of viral replication (4,5).…”

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confidence: 99%

Human Papillomavirus Episome Stability Is Reduced by Aphidicolin and Controlled by DNA Damage Response Pathways

Edwards

Helmus

Koeller

et al. 2013

J Virol

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A highly reproducible quantitative PCR (Q-PCR) assay was used to study the stability of human papillomavirus (HPV) in undifferentiated keratinocytes that maintain viral episomes. The term "stability" refers to the ability of episomes to persist with little copy number variation in cells. In investigating the mechanism of action of PA25, a previously published compound that destabilizes HPV episomes, aphidicolin was also found to markedly decrease episome levels, but via a different pathway from that of PA25. Since aphidicolin is known to activate DNA damage response (DDR) pathways, effects of inhibitors and small interfering RNAs (siRNAs) acting within DDR pathways were investigated. Inhibitors of Chk1 and siRNA directed against ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia Rad3-related (ATR) pathways significantly reduced viral episomes, suggesting that these pathways play a role in maintaining HPV episome stability. Inhibitors of Chk2 and DNA-PK had no effect on episome levels. Pharmacological inhibition of ATM proteins had no effect on episome levels, but ATM knockdown by siRNA significantly reduced episome levels, suggesting that ATM proteins are playing an important role in HPV episome stability that does not require kinase activity. These results outline two pathways that trigger episome loss from cells and suggest the existence of a littleunderstood mechanism that mediates viral DNA elimination. Together, our results also indicate that HPV episomes have a stability profile that is remarkably similar to that of fragile sites; these similarities are outlined and discussed. This close correspondence may influence the preference of HPV for integration into fragile sites.

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“…E1 is a viral enzyme with ATPase and helicase activity [32,33]. E2 is a DNA-binding protein involved in activation or repression of diferent HPV promoters [34,35]. As the infected cell migrates toward the supericial layers of the squamous epithelium, the viral genome gets integrated into the cellular …”

Section: Life Cycle Of Hpv Infectionmentioning

confidence: 99%

“…E2 is a DNA-binding protein involved in activation or repression of diferent HPV promoters [35], and it also has a relevant role in controlling migration of viral DNA to daughter cells during mitosis of infected cells [87]. Due to these functions, E2 is expressed in all stages of the infection (Figure 2).…”

Section: Therapeutic Vaccinesmentioning

confidence: 99%

Prophylactic and Therapeutic Vaccines against Human Papillomavirus Infections

Rosales¹,

Rosales²

2017

Vaccines

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Human papillomaviruses (HPVs) are a large family of double-strand DNA viruses comprising more than 180 types. Infection with HPV is associated with benign and malignant proliferation of skin and mucosae. Low-risk HPVs produce warts, whereas high-risk viruses induce tumors. Because there are no anti-viral drugs for HPV infection, there is a lot of interest in vaccines that can prevent the infection and also in vaccines that can be used to treat established infections and HPV-related tumors. Two prophylactic vaccines have been approved for preventing HPV infection. They seem to be efective when very young people are vaccinated. Unfortunately, many older people are still at risk of infection, mainly in countries where vaccination coverage is not eicient and for those people, novel therapeutic vaccines are being developed. This chapter describes the properties of HPV vaccines used today and the current status of several therapeutic vaccines been developed to treat HPV-induced lesions.

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The Papillomavirus E2 proteins

Cited by 349 publications

References 285 publications

Human Papillomavirus E2 Regulates SRSF3 (SRp20) To Promote Capsid Protein Expression in Infected Differentiated Keratinocytes

Human Papillomavirus E2 Regulates SRSF3 (SRp20) To Promote Capsid Protein Expression in Infected Differentiated Keratinocytes

Human Papillomavirus Episome Stability Is Reduced by Aphidicolin and Controlled by DNA Damage Response Pathways

Prophylactic and Therapeutic Vaccines against Human Papillomavirus Infections

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