Involvement of Brd4 in different steps of the papillomavirus life cycle

Iftner, Thomas; Haedicke‐Jarboui, Juliane; Wu, Shwu Yuan; Chiang, Cheng Ming

doi:10.1016/j.virusres.2016.12.006

Cited by 51 publications

(62 citation statements)

References 65 publications

(109 reference statements)

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“…HPV-31 E2 Y138E does not bind the C-terminal domain of Brd4. The E2 binding partner Brd4 has been previously shown to regulate several phases of the viral life cycle through binding of its C-terminal domain (CTD; aa 1222 to 1362) to the E2 transactivation domain (18,(23)(24)(25)(26)(27)(28). The E2 DNA binding domain has also been reported to bind a basic residue-enriched interaction domain (BID) within amino acids 524 to 579 of Brd4 and to bind to the phosphorylation-dependent interaction domain (PDID) formed by amino acids 287 to 530 (18).…”

Section: Resultsmentioning

confidence: 99%

Phosphorylation of a Conserved Tyrosine in the Papillomavirus E2 Protein Regulates Brd4 Binding and Viral Replication

DeSmet

Jose

Isaq

et al. 2019

J Virol

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The papillomavirus (PV) E2 protein coordinates viral transcription and genome replication. Following a strategy to identify amino acids in E2 that are posttranslationally modified, we reported that tyrosine kinase fibroblast growth factor receptor 3 (FGFR3) complexes with and phosphorylates E2, which inhibits viral DNA replication. Here, we present several lines of evidence indicating that tyrosine (Y) 138 of HPV-31 E2 is a substrate of FGFR3. The active form of FGFR3 bound to and phosphorylated the region of amino acids (aa) 107 to 175 in HPV-31 E2. The E2 phenylalanine (F) mutant Y138F displayed reduced FGFR3-induced phosphotyrosine. A constitutive kinase-active FGFR3 inhibited wild-type (WT) E2-induced E1-dependent DNA replication, while the 138F mutant retained activity. The tyrosine to glutamic acid (E) mutant Y138E, which can mimic phosphotyrosine, failed to induce transient DNA replication, although it maintained the ability to bind and localize the viral DNA helicase E1 to the viral origin. The bromodomain-containing protein 4 (Brd4) binds to E2 and is necessary for initiation of viral DNA synthesis. Interestingly, the Y138E protein coimmunoprecipitated with full-length Brd4 but was defective for association with its C-terminal domain (CTD). These results imply that the activity of the FGFR3 kinase in the infected epithelial cell restricts the HPV replication program through phosphorylation of E2 at Y138, which interferes with E2 binding to the Brd4 CTD, and that this interaction is required for initiation of viral DNA synthesis. IMPORTANCE Human papillomaviruses (HPVs) are highly infectious pathogens that commonly infect the oropharynx and uterine cervix. The idea that posttranslational modifications of viral proteins coordinates viral genome replication is less explored. We recently discovered that fibroblast growth factor receptor 3 (FGFR3) phosphorylates the viral E2 protein. The current study demonstrates that FGFR3 phosphorylates E2 at tyrosine 138, which inhibits association with the C-terminal peptide of Brd4. This study illustrates a novel regulatory mechanism of virus-host interaction and provides insight into the role of Brd4 in viral replication.

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Section: Resultsmentioning

confidence: 99%

Phosphorylation of a Conserved Tyrosine in the Papillomavirus E2 Protein Regulates Brd4 Binding and Viral Replication

DeSmet

Jose

Isaq

et al. 2019

J Virol

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“…Brd4 is important for regulation of the HPV early promoter and viral DNA replication (Iftner et al, 2016; Schweiger et al, 2006; Wang et al, 2013; Yan et al, 2010). To determine whether Brd4 or another BET family protein has a functional role in late promoter activation, we cultured cells containing episomal HPV16 genomes in monolayer or MC in the presence or absence of JQ1, which interacts with the bromodomains of BET family proteins and prevents binding to acetylated chromatin (Filippakopoulos et al, 2010).…”

Section: Resultsmentioning

confidence: 99%

“…Although JQ1 can inhibit other BET family proteins, we chose to focus on Brd4 because of its involvement in elongation and its known role in HPV transcriptional regulation (reviewed in Iftner et al, 2016). To determine whether Brd4 might directly regulate the late promoter, ChIP analysis was performed.…”

Section: Resultsmentioning

confidence: 99%

“…Because of its ability to recruit P-TEFb to promoters (Hargreaves et al, 2009; Kohoutek, 2009) and its known association with HPV (Iftner et al, 2016), we chose to focus on Brd4. Brd4 regulates the HPV early promoter and viral DNA replication (Iftner et al, 2016; Schweiger et al, 2006; Wang et al, 2013; Yan et al, 2010), and the viral E2 repressor protein disrupts the interaction between Brd4 and P-TEFb (Yan et al, 2010). A mutation in E2 that prevents binding to Brd4 also prevents episomal maintenance of HPV16 (Gauson et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Brd4 is one of several members of the bromodomain and extra-terminal domain (BET) family of transcriptional regulatory proteins, but Brd4 is the family member most associated with HPV (reviewed in (Iftner et al, 2016)). Brd4 binds to and regulates the HPV early promoter (Schweiger et al, 2006; Wu et al, 2006; Wu et al, 2016; Yan et al, 2010) and viral genome replication (Wang et al, 2013; Wu et al, 2016; You et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Regulation of the human papillomavirus type 16 late promoter by transcriptional elongation

2017

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Transcripts from the late promoter of human papillomavirus type 16 (HPV16) are upregulated upon host cell differentiation. Differentiation-dependent transcript regulation is thought to sequester viral antigens in the uppermost epithelial layers, facilitating immune evasion. The mechanisms regulating late promoter upregulation during differentiation are poorly characterized. We show that the late promoter is upregulated at the transcriptional level and that the viral enhancer stimulates promoter activity. Using kinase inhibition and chromatin immunoprecipitation analysis, we show evidence for differentiation-dependent enhancement of transcript elongation. Three factors that promote transcript elongation, cyclin dependent kinase 9 (CDK9), CDK8 (a subunit of the Mediator complex), and bromodomain containing protein 4 (Brd4) are recruited to viral genomes upon differentiation, and each plays a role in promoter activity. These results shed light on the transcriptional processes utilized by HPV16 for proper regulation of gene expression during the viral life cycle.

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The homeobox transcription factor HOXC13 upregulates human papillomavirus E1 gene expression and contributes to viral genome maintenance

2019

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Human papillomavirus (HPV) infects the basal cells of epithelia and maintains its genome stably as episomes. However, the mechanisms of viral genome maintenance are not fully understood. Here, using normal human immortalized keratinocytes (NIKS), we identified the homeobox transcription factor HOXC13 as a critical host factor for retaining the copy number of HPV genomes in the cell. HOXC13 knockdown in NIKS significantly decreased mRNA levels of the E1 gene, which encodes a DNA helicase required for HPV genome replication, accompanied by a reduction of the viral genome copy number. Chromatin immunoprecipitation assays revealed HOXC13 binding to the long control region that regulates E1 expression. These results indicate that HOXC13 plays invaluable roles in maintaining HPV persistent infection through E1 gene upregulation.

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Involvement of Brd4 in different steps of the papillomavirus life cycle

Cited by 51 publications

References 65 publications

Phosphorylation of a Conserved Tyrosine in the Papillomavirus E2 Protein Regulates Brd4 Binding and Viral Replication

Phosphorylation of a Conserved Tyrosine in the Papillomavirus E2 Protein Regulates Brd4 Binding and Viral Replication

Regulation of the human papillomavirus type 16 late promoter by transcriptional elongation

The homeobox transcription factor HOXC13 upregulates human papillomavirus E1 gene expression and contributes to viral genome maintenance

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