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

Klymenko, Tetyana; Hernandez-Lopez, Hegel; MacDonald, Alasdair A.; Bodily, Jason M.; Graham, Sheila V.

doi:10.1128/jvi.03073-15

Cited by 35 publications

(61 citation statements)

References 55 publications

(96 reference statements)

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“…Specifically, HPV16 and HPV31 E2 can transcriptionally upregulate the expression of at least SRSF1, -2, and -3 ( Fig. 1D) (31). This exciting finding implies that because the relative levels of SRSFs in a cell determine alternative splicing outcomes and thus the overall protein profile, E2 may control the cellular environment via control of SRSF expression to optimize viral replication.…”

Section: E2 As a Regulator Of Srsfsmentioning

confidence: 82%

Human Papillomavirus E2 Protein: Linking Replication, Transcription, and RNA Processing

Graham

2016

J Virol

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The human papillomavirus (HPV) life cycle is tightly linked to differentiation of the infected epithelium. This means that viral proteins must exert control over epithelial gene expression in order to optimize viral production. The HPV E2 protein controls replication, transcription, and viral genome partitioning during the viral infectious life cycle. It consists of a nucleic acid-binding domain and a protein-protein interaction domain separated by a flexible serine and arginine-rich hinge region. Over the last few years, mounting evidence has uncovered an important new role for E2 in viral and cellular RNA processing. This Gem discusses the role of E2 in controlling the epithelial cellular environment and how E2 might act to coordinate late events in the viral replication cycle. HUMAN PAPILLOMAVIRUS LIFE CYCLEH uman papillomaviruses (HPVs) are small (ϳ8.0-kbp) circular double-stranded DNA viruses that infect epithelial cells (keratinocytes) (1). There are more than 200 HPV genotypes. For the most part, HPVs of the ␣-genotype group infect mucosal epithelia, while the ␤-genotypes infect predominantly cutaneous epithelia (2). Most HPV infections are asymptomatic, or they manifest as benign lesions or warts. They are usually transient and are eventually cleared by the immune system (3). Despite this, HPVs cause a high burden of clinically significant disease worldwide, because the anogenital mucosa-infective high-risk group of HPVs (HR-HPVs) can cause persistent infection that leads to epithelial dysplasia and neoplasia. HR-HPVs are commonly associated with cervical cancer and tumors of other anogenital sites (2). Per annum, worldwide, there are around 500,000 new cases of cervical disease, and around 270,000 women die from cervical cancer. The two most prevalent HR-HPVs are HPV16 and -18, which are targeted by the current HPV vaccines (4). Over the last few decades, epidemic HR-HPV infection, especially in men, has been associated with a significant increase in oropharyngeal cancers (5). Certain cutaneous HPVs can also cause tumors (squamous cell carcinomas) in immunocompromised or immunosuppressed individuals (6). Thus, the causative association of HPV infection with a number of significant cancers indicates that increased understanding of the viral life cycle is essential.The HPV life cycle is intimately linked to epithelial differentiation (Fig. 1A) (2). HPV normally infects dividing cells at the base of the epithelium (basal layer) but completes its life cycle by amplifying progeny DNA genomes in the midepithelial layers (spinous layer) and carrying out viral encapsidation in the uppermost epithelial layer (granular layer) (Fig. 1A). Viral production is achieved through a highly orchestrated and complex viral gene expression program (Fig. 1A) (2). Mature virions are released upon shedding and disintegration of dead superficial epithelial cells into the environment. As a necessity, HPV infection alters the normal differentiation pattern of the epithelium and controls cellular gene expression to support viral re...

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Section: E2 As a Regulator Of Srsfsmentioning

confidence: 82%

Human Papillomavirus E2 Protein: Linking Replication, Transcription, and RNA Processing

Graham

2016

J Virol

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“…This suggests that although the late region can be transcribed in less differentiated cells, RNA processing or export from the nucleus is inhibited, or cytoplasmic late mRNAs are highly unstable. Late pre-mRNAs may be synthesised in less differentiated keratinocytes, at least in the W12 and NIKS16 models of the virus life cycle, because it is possible to induce L1 protein expression by manipulating levels of certain RNA-binding proteins [ 92 , 98 ]. Moreover, expression of reporter constructs containing the entire wild type HPV16 late regulatory element gave significantly increased RNA nuclear retention compared to similar constructs with mutations affecting key protein-binding regions of the element [ 97 ].…”

Section: Differentiation-dependent Regulation Of Polyadenylationmentioning

confidence: 99%

“…In general, cellular and viral splicing is positively controlled by SR splicing factors [ 108 ], and negatively by hnRNP proteins [ 109 , 110 ]. HPV controls expression of SRSF1, 2 and 3 through the viral E2 transcription factor [ 98 ] and SRSF levels peak in the mid to upper layers of HPV-infected epithelial [ 75 , 98 ] where late gene expression commences [ 23 ], and E2 is most highly expressed [ 32 , 33 ]. Recently, we reported that SRSF3 controls L1 protein expression in a differentiation-dependent manner.…”

Section: Differentiation-dependent Regulation Of Polyadenylationmentioning

confidence: 99%

Keratinocyte Differentiation-Dependent Human Papillomavirus Gene Regulation

Graham

2017

Viruses

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Human papillomaviruses (HPVs) cause diseases ranging from benign warts to invasive cancers. HPVs infect epithelial cells and their replication cycle is tightly linked with the differentiation process of the infected keratinocyte. The normal replication cycle involves an early and a late phase. The early phase encompasses viral entry and initial genome replication, stimulation of cell division and inhibition of apoptosis in the infected cell. Late events in the HPV life cycle include viral genome amplification, virion formation, and release into the environment from the surface of the epithelium. The main proteins required at the late stage of infection for viral genome amplification include E1, E2, E4 and E5. The late proteins L1 and L2 are structural proteins that form the viral capsid. Regulation of these late events involves both cellular and viral proteins. The late viral mRNAs are expressed from a specific late promoter but final late mRNA levels in the infected cell are controlled by splicing, polyadenylation, nuclear export and RNA stability. Viral late protein expression is also controlled at the level of translation. This review will discuss current knowledge of how HPV late gene expression is regulated.

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“…However, to date only a limited number of genes are validated to be regulated by E2. These include MMP-9 (Behren et al, 2005), hTERT (Lee et al, 2002), SF2/ASF (Klymenko et al, 2016; Mole et al, 2009), IL-10 (Bermudez-Morales et al, 2011), p21 (Steger et al, 2002), involucrin (Hadaschik et al, 2003), β 4-integrin (Oldak et al, 2010) and most recently c-Fos (Delcuratolo et al, 2016). Brd4 is necessary for E2’s function as a transcriptional activator when E2BS is positioned away from the promoter-proximal region in an enhancer-like sequence context (Lee and Chiang, 2009) as found in CRPV (see Fig.…”

Section: Brd4 and E2 In The Regulation Of Cellular Genes And Theirmentioning

confidence: 99%

Involvement of Brd4 in different steps of the papillomavirus life cycle

Iftner¹,

Haedicke‐Jarboui²,

et al. 2017

Virus Research

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Bromodomain-containing protein 4 (Brd4) is a cellular chromatin-binding factor and transcriptional regulator that recruits sequence-specific transcription factors and chromatin modulators to control target gene transcription. Papillomaviruses (PVs) have evolved to hijack Brd4’s activity in order to create a facilitating environment for the viral life cycle. Brd4, in association with the major viral regulatory protein E2, is involved in multiple steps of the PV life cycle including replication initiation, viral gene transcription, and viral genome segregation and maintenance. Phosphorylation of Brd4, regulated by casein kinase II (CK2) and protein phosphatase 2A (PP2A), is critical for viral gene transcription as well as E1- and E2-dependent origin replication. Thus, pharmacological agents regulating Brd4 phosphorylation and inhibitors blocking phospho-Brd4 functions are promising candidates for therapeutic intervention in treating human papillomavirus (HPV) infections as well as associated disease.

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

Cited by 35 publications

References 55 publications

Human Papillomavirus E2 Protein: Linking Replication, Transcription, and RNA Processing

Human Papillomavirus E2 Protein: Linking Replication, Transcription, and RNA Processing

Keratinocyte Differentiation-Dependent Human Papillomavirus Gene Regulation

Involvement of Brd4 in different steps of the papillomavirus life cycle

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