Papillomavirus E2 protein is regulated by specific fibroblast growth factor receptors

DeSmet, Marsha; Kanginakudru, Sriramana; Jose, Leny; Xie, Fang; Gilson, Timra; Androphy, Elliot J.

doi:10.1016/j.virol.2018.05.013

Cited by 8 publications

(15 citation statements)

References 34 publications

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“…In contrast, another E2 interaction partner, FGFR2, reduced transient replication with Y138F ( Fig. 1C) (20). We previously reported that coexpression of the constitutively kinase-active FGFR3 K650E suppresses HPV-31 E1-and E2-mediated transient replication, so the Y138E result was consistent with this phenotype (12).…”

Section: Resultssupporting

confidence: 73%

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: Resultssupporting

confidence: 73%

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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“…Of the 90 known tyrosine kinases, a consensus sequence is only recognized for LCK, Abl, Src, ALK, and EGFR (38). HPV-31 E2 Y102 fits the epidermal growth factor receptor (EGFR) consensus sequence, but our previous observations that E2 does not bind EGFR and that EGFR does not inhibit replication (40) imply that EGFR is not the kinase for Y102. The kinase that phosphorylates BPV-1 may differ from HPV-31, as the sequence flanking Y102 differs significantly (Fig.…”

Section: Discussionmentioning

confidence: 93%

“…The kinase which phosphorylates at position 102 has yet to be identified. We previously published that that the FGFRs associate with E2 (40,42), though none of these phosphorylate at Y102. Of the 90 known tyrosine kinases, a consensus sequence is only recognized for LCK, Abl, Src, ALK, and EGFR (38).…”

Section: Discussionmentioning

confidence: 99%

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Human Papillomavirus 31 Tyrosine 102 Regulates Interaction with E2 Binding Partners and Episomal Maintenance

Gilson

Culleton

Xie

et al. 2020

J Virol

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Several serine and threonine residues of the papilloma virus early E2 protein have been found to be phosphorylated. By contrast, only one E2 tyrosine phosphorylation site in BPV-1 (tyrosine 102) and one HPV-16/31 (tyrosine 138) site have been characterized. Between BPV-1 and HPV-31 E2, 8 of the 11 tyrosines are conserved in the N-terminal domain, suggesting that phosphorylation of tyrosines has an essential role in E2 biology. In this paper we examine the effect of Y102 phosphorylation on HPV-31 E2 biology. Y102 proteins mutated either to the potential phospho-mimetic glutamic acid (Y102E) or to the non-phosphorylated homologue phenylalanine (Y102F) remain nuclear; however, Y102E is more associated with the nuclear matrix fraction. This is consistent with the inability of Y102E to bind TopBP1. Both BPV-1 and HPV-31 Y102E are similar in that neither bind the C-terminus of Brd4, but in all other aspects, the mutant behaves differently between the two families of papillomaviruses. BPV-1 Y102E was unable to bind E1 and did not replicate in a transient in-vitro assay, while HPV-31 Y102E binds E1 and replicated albeit at lower levels than wild type. To examine effect of E2 mutations under more native-like infection conditions, a neomycin selectable marker was inserted into L1/L2 of HPV-31 genome, creating HPV-31neo. This genome was maintained in every cell line tested for at least 50 days post-transfection/infection. Y102E in both transfection and infection conditions was unable to maintain high episome copy numbers in epithelial cell lines. IMPORTANCE Post-translational modifications by phosphorylation can change protein activities, binding partners, or localization. Tyrosine 102 is conserved between delta papillomavirus BPV-1 and alpha papillomavirus HPV-31 E2. We characterized mutations of HPV-31 E2 for interactions with relevant cellular binding partners and replication in the context of the viral genome.

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“…Protein phosphorylation is a reversible post-translational modification, often regulatory in nature, and is fundamental to cell signaling mechanisms. The HPV-8, HPV-11, HPV-16, HPV-31, bovine papillomavirus (BPV-1) and cottontail rabbit papillomavirus (CRPV) E2 proteins are phosphoproteins [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. The first phosphorylations within E2 were identified on serine 298 and 301 residues, located in the non-conserved hinge region of BPV-1 E2, by peptide mapping and site-directed mutagenesis [ 16 ].…”

Section: Serine/threonine Phosphorylationmentioning

confidence: 99%

Regulation of the Human Papillomavirus Lifecyle through Post-Translational Modifications of the Viral E2 Protein

et al. 2021

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The human papillomavirus (HPV) is a DNA tumor virus that infects cutaneous and mucosal epithelia where high-risk (HR) HPV infections lead to cervical, oropharyngeal, and anogenital cancers. Worldwide, nearly 5% of all cancers are caused by HR HPV. The viral E2 protein is essential for episomal replication throughout the viral lifecycle. The E2 protein is regulated by phosphorylation, acetylation, sumoylation, and ubiquitination. In this mini-review, we summarize the recent advancements made to identify post translational modifications within E2 and their ability to control viral replication.

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Papillomavirus E2 protein is regulated by specific fibroblast growth factor receptors

Cited by 8 publications

References 34 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

Human Papillomavirus 31 Tyrosine 102 Regulates Interaction with E2 Binding Partners and Episomal Maintenance

Regulation of the Human Papillomavirus Lifecyle through Post-Translational Modifications of the Viral E2 Protein

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