Interaction between human papillomavirus type 5 E2 and polo‐like kinase 1

Wang, Weisheng; Lee, Moon‐Sing; Tseng, Chih-En; Liao, I-Huan; Huang, Shuping; Lin, Ru-Inn; Li, Chin

doi:10.1002/jmv.21404

Cited by 9 publications

(7 citation statements)

References 47 publications

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“…This suggests that SRPK1 phosphorylation may have a role in regulating the cellular localization of HPV1 E2. Indeed, SRPK1 activity is associated with the release of HPV5 E2 from nuclear speckles and transport to the cytoplasm (42,43). Since E2 stability is sensitive to phosphorylation (44), an alternative explanation is that SRPK1 phosphorylation of the E2 hinge regulates the stability of the fraction of E2 protein that is located within the nucleolus.…”

Section: Discussionmentioning

confidence: 99%

“…For example, the HPV5 E2 hinge region contains 27 RS/SR motifs. The HPV5 E2 protein has been shown to be a substrate for SRPK1 in vitro, and evidence suggests that this phosphorylation is restricted to the hinge region (42,43). Examination of the sequence of the HPV1 E2 hinge region identified four RS/SR dipeptide motifs, with the serines at positions 265, 267, 281, and 306 (Fig.…”

Section: Hpv1 E1^e4 Inhibits Srpk1 Phosphorylation Of Cellular Srmentioning

confidence: 97%

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Human Papillomavirus Type 1 E1^E4 Protein Is a Potent Inhibitor of the Serine-Arginine (SR) Protein Kinase SRPK1 and Inhibits Phosphorylation of Host SR Proteins and of the Viral Transcription and Replication Regulator E2

Prescott

Brimacombe

Hartley

et al. 2014

J Virol

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The serine-arginine-specific protein kinase SRPK1 is a common binding partner of the E1^E4 protein of diverse human papillomavirus types. We show here for the first time that the interaction between HPV1 E1^E4 and SRPK1 leads to potent inhibition of SRPK1 phosphorylation of host serine-arginine (SR) proteins that have critical roles in mRNA metabolism, including pre-mRNA processing, mRNA export, and translation. Furthermore, we show that SRPK1 phosphorylates serine residues of SR/RS dipeptides in the hinge region of the HPV1 E2 protein in in vitro kinase assays and that HPV1 E1^E4 inhibits this phosphorylation. After mutation of the putative phosphoacceptor serine residues, the localization of the E2 protein was altered in primary human keratinocytes; with a significant increase in the cell population showing intense E2 staining of the nucleolus. A similar effect was observed following coexpression of E2 and E1^E4 that is competent for inhibition of SRPK1 activity, suggesting that the nuclear localization of E2 is sensitive to E1^E4-mediated SRPK1 inhibition. Collectively, these data suggest that E1^E4-mediated inhibition of SRPK1 could affect the functions of host SR proteins and those of the virus transcription/replication regulator E2. We speculate that the novel E4 function identified here is involved in the regulation of E2 and SR protein function in posttranscriptional processing of viral transcripts. IMPORTANCEThe HPV life cycle is tightly linked to the epithelial terminal differentiation program, with the virion-producing phase restricted to differentiating cells. While the most abundant HPV protein expressed in this phase is the E4 protein, we do not fully understand the role of this protein. Few E4 interaction partners have been identified, but we had previously shown that E4 proteins from diverse papillomaviruses interact with the serine-arginine-specific protein kinase SRPK1, a kinase important in the replication cycles of a diverse range of DNA and RNA viruses. We show that HPV1 E4 is a potent inhibitor of this host cell kinase. We show that E4 inhibits SRPK1 phosphorylation, not only of cellular SR proteins involved in regulating alternative splicing of RNA but also the viral transcription/replication regulator E2. Our findings reveal a potential E4 function in regulation of viral late gene expression through the inhibition of a host cell kinase. H uman papillomaviruses (HPVs) cause hyperproliferative warts and papillomas of the squamous epithelium at different body sites. Infection of the anogenital tract and oropharynx can lead to benign and malignant disease. There are 13 HPV types defined as causative agents of cancers at these sites, the most common being HPV 16 (HPV16) and HPV18. Of the viruses that infect cutaneous surfaces, some, such as HPV1, cause only benign warts, while infection with others, such as HPV5 and HPV8, can, in immunocompromised individuals, cause the formation of lesions that are at risk of malignant conversion.Despite the heterogeneity in pathogenesis, HPVs show a ...

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Section: Discussionmentioning

confidence: 99%

Section: Hpv1 E1^e4 Inhibits Srpk1 Phosphorylation Of Cellular Srmentioning

confidence: 97%

Human Papillomavirus Type 1 E1^E4 Protein Is a Potent Inhibitor of the Serine-Arginine (SR) Protein Kinase SRPK1 and Inhibits Phosphorylation of Host SR Proteins and of the Viral Transcription and Replication Regulator E2

Prescott

Brimacombe

Hartley

et al. 2014

J Virol

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“…PLK1-mediated P protein phosphorylation downregulates viral gene expression and thereby avoids efficient induction of the host innate immune response [34]. Furthermore, the interaction of the E2 protein of human papillomavirus type 5 with PLK1 was reported to inhibit Brd4 phosphorylation by PLK1, thereby interfering with cellular functions of Brd4 in promoting cell cycle progression from the G1 to the S phases [35]. Finally, binding of PLK1 to the NS5A protein of hepatitis C virus and its hyperphosphorylation by PLK1 is important for efficient virus replication [36].…”

Section: Introductionmentioning

confidence: 99%

Interactions of Prototype Foamy Virus Capsids with Host Cell Polo-Like Kinases Are Important for Efficient Viral DNA Integration

et al. 2016

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Unlike for other retroviruses, only a few host cell factors that aid the replication of foamy viruses (FVs) via interaction with viral structural components are known. Using a yeast-two-hybrid (Y2H) screen with prototype FV (PFV) Gag protein as bait we identified human polo-like kinase 2 (hPLK2), a member of cell cycle regulatory kinases, as a new interactor of PFV capsids. Further Y2H studies confirmed interaction of PFV Gag with several PLKs of both human and rat origin. A consensus Ser-Thr/Ser-Pro (S-T/S-P) motif in Gag, which is conserved among primate FVs and phosphorylated in PFV virions, was essential for recognition by PLKs. In the case of rat PLK2, functional kinase and polo-box domains were required for interaction with PFV Gag. Fluorescently-tagged PFV Gag, through its chromatin tethering function, selectively relocalized ectopically expressed eGFP-tagged PLK proteins to mitotic chromosomes in a Gag STP motif-dependent manner, confirming a specific and dominant nature of the Gag-PLK interaction in mammalian cells. The functional relevance of the Gag-PLK interaction was examined in the context of replication-competent FVs and single-round PFV vectors. Although STP motif mutated viruses displayed wild type (wt) particle release, RNA packaging and intra-particle reverse transcription, their replication capacity was decreased 3-fold in single-cycle infections, and up to 20-fold in spreading infections over an extended time period. Strikingly similar defects were observed when cells infected with single-round wt Gag PFV vectors were treated with a pan PLK inhibitor. Analysis of entry kinetics of the mutant viruses indicated a post-fusion defect resulting in delayed and reduced integration, which was accompanied with an enhanced preference to integrate into heterochromatin. We conclude that interaction between PFV Gag and cellular PLK proteins is important for early replication steps of PFV within host cells.

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“…We have previously shown that the hinge of HPV8 E2 is highly phosphorylated, and the majority of this phosphorylation is likely to be of the many SR/RS dipeptides located here . SRPK1 can phosphorylate the hinge region of HPV5 and HPV8 E2 proteins in vitro . Prescott et al.…”

Section: Resultsmentioning

confidence: 89%

A proteomic approach to discover and compare interacting partners of papillomavirus E2 proteins from diverse phylogenetic groups

2015

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Papillomaviruses are a very successful group of viruses that replicate persistently in localized regions of the stratified epithelium of their specific host. Infection results in pathologies ranging from asymptomatic infection, benign warts, to malignant carcinomas. Despite this diversity, papillomavirus genomes are small (7-8 kbp) and contain at most eight genes. To sustain the complex papillomaviral life cycle, each viral protein has multiple functions and interacts with and manipulates a plethora of cellular proteins. In this study, we use tandem affinity purification and mass spectrometry to identify host factors that interact with eleven different papillomavirus E2 proteins from diverse phylogenetic groups. The E2 proteins function in viral transcription and replication and correspondingly interact with host proteins involved in transcription, chromatin remodeling and modification, replication and RNA processing.

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Interaction between human papillomavirus type 5 E2 and polo‐like kinase 1

Cited by 9 publications

References 47 publications

Human Papillomavirus Type 1 E1^E4 Protein Is a Potent Inhibitor of the Serine-Arginine (SR) Protein Kinase SRPK1 and Inhibits Phosphorylation of Host SR Proteins and of the Viral Transcription and Replication Regulator E2

Human Papillomavirus Type 1 E1^E4 Protein Is a Potent Inhibitor of the Serine-Arginine (SR) Protein Kinase SRPK1 and Inhibits Phosphorylation of Host SR Proteins and of the Viral Transcription and Replication Regulator E2

Interactions of Prototype Foamy Virus Capsids with Host Cell Polo-Like Kinases Are Important for Efficient Viral DNA Integration

A proteomic approach to discover and compare interacting partners of papillomavirus E2 proteins from diverse phylogenetic groups

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