Serine/arginine-rich protein 30c activates human papillomavirus type 16 L1 mRNA expression via a bimodal mechanism

Somberg, Monika; Li, Xiaoze; Johansson, Cecilia; Orru, Beatrice; Chang, Roger; Rush, Margaret; Fay, Joanna; Ryan, Fergus; Schwartz, Stefan

doi:10.1099/vir.0.033183-0

Cited by 32 publications

(39 citation statements)

References 37 publications

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“…Further, wild-type HPV genomes are present in NIKS16 and W12E and CIN612-9E cells. In contrast, in the previous studies, subgenomic constructs with deletions in important cis-acting elements (e.g., the late negative regulatory region [51]) controlling gene expression were used (20,21,50). In our HPV-infected lines, viral transcription is driven from the natural viral promoters (10,38) which are relatively weakly active.…”

Section: Discussionmentioning

confidence: 99%

“…SRSF3 also controls HPV16 oncoprotein expression (19), but to a lesser extent than SRSF2 (23). SRSF9 can activate the E4 splice donor 3632 while inhibiting splice acceptor 3358 at the 5= end of the E4 open reading frame (21). Of interest, another splicing control element in the E4 coding region (50) binds SRSF3 (19).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies that have examined SR protein regulation of viral RNA splicing in tumor cells transiently expressing subgenomic reporter constructs have demonstrated that SRSF1 controls expression of early and late viral mRNAs (20,22), while SRSF3 can regulate BPV1 and HPV16 early and late gene expression (19). SRSF9 can also control HPV16 late gene expression (21).…”

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confidence: 99%

“…Previous data have demonstrated the importance of a number of these proteins in production of HPV mRNAs (18). SRSF1 (SF2/ ASF), SRSF3 (SRp20), and SRSF9 (SRp30c) have been shown to bind viral mRNAs in the E4 open reading frame (19)(20)(21)(22). SRSF2 (SC35) and SRSF3 have been shown to control production of the viral E6 and E7 oncoprotein mRNAs (19,23).…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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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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“…Cellular SR proteins seem to have a pivotal role in these events and in fact E2 from the high-risk virus HPV16 has been shown to regulate the transcription of some of these factors (52)(53)(54)(55). Selection of bovine and human papillomavirus late-specific splice sites has been shown to be controlled by SRSF3, with this cellular factor suppressing the activity of a key exonic splicing enhancer in the papillomavirus genomes (56).…”

Section: Discussionmentioning

confidence: 99%

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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RNA elements that control human papillomavirus mRNA splicing‐targets for therapy?

Schwartz,

Wu,

Kajitani

2024

Journal of Medical Virology

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Human papillomaviruses (HPVs) cause more than 4.5% of all cancer in the world and more than half of these cases are attributed to human papillomavirus type 16 (HPV16). Prophylactic vaccines are available but antiviral drugs are not. Novel targets for therapy are urgently needed. Alternative RNA splicing is extensively used by HPVs to express all their genes and HPV16 is no exception. This process must function to perfection since mis‐splicing could perturb the HPV gene expression program by altering mRNA levels or by generating dysfunctional mRNAs. Cis‐acting RNA elements on the viral mRNAs and their cognate cellular trans‐acting factors control papillomavirus RNA splicing. The precise but delicate nature of the splicing process renders splicing sensitive to interference. As such, papillomavirus RNA splicing is a potential target for therapy. Here we summarize our current understanding of cis‐acting HPV16 RNA elements that control HPV16 mRNA splicing via cellular proteins and discuss how they may be exploited as targets for therapy to papillomavirus infections and cancer.

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Serine/arginine-rich protein 30c activates human papillomavirus type 16 L1 mRNA expression via a bimodal mechanism

Cited by 32 publications

References 37 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 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

RNA elements that control human papillomavirus mRNA splicing‐targets for therapy?

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