Human Papillomavirus 16 Oncoprotein Expression Is Controlled by the Cellular Splicing Factor SRSF2 (SC35)

McFarlane, Melanie; MacDonald, Alasdair A.; Stevenson, Andrew; Graham, Sheila V.

doi:10.1128/jvi.03434-14

Cited by 48 publications

(49 citation statements)

References 54 publications

(83 reference statements)

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“…SRSF2 controls HPV16 oncoprotein expression by regulating mRNA stability (23). 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).…”

Section: Discussionmentioning

confidence: 99%

“…Apart from these (20). SRSF2 controls HPV16 oncoprotein expression by regulating mRNA stability (23). SRSF3 also controls HPV16 oncoprotein expression (19), but to a lesser extent than SRSF2 (23).…”

Section: Discussionmentioning

confidence: 99%

“…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). 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).…”

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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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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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“…Host splicing factors and some viral proteins responsible for the regulation of BPV-1 (5,6,47) and HPV16 (11,18,48,53) RNA splicing have been extensively studied. In this report, we further reveal that the host splicing factors responsible for two major splicing events in HPV18 are hnRNP A1 and SRSF3.…”

Section: Discussionmentioning

confidence: 99%

Serine/Arginine-Rich Splicing Factor 3 and Heterogeneous Nuclear Ribonucleoprotein A1 Regulate Alternative RNA Splicing and Gene Expression of Human Papillomavirus 18 through Two Functionally Distinguishable cis Elements

Ajiro

Tang

Doorbar

et al. 2016

J Virol

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Human papillomavirus 18 (HPV18) is the second most common oncogenic HPV type associated with cervical, anogenital, and oropharyngeal cancers. Like other oncogenic HPVs, HPV18 encodes two major (one early and one late) polycistronic premRNAs that are regulated by alternative RNA splicing to produce a repertoire of viral transcripts for the expression of individual viral genes. However, RNA cis-regulatory elements and trans-acting factors contributing to HPV18 alternative RNA splicing remain unknown. In this study, an exonic splicing enhancer (ESE) in the nucleotide (nt) 3520 to 3550 region in the HPV18 genome was identified and characterized for promotion of HPV18 929^3434 splicing and E1^E4 production through interaction with SRSF3, a host oncogenic splicing factor differentially expressed in epithelial cells and keratinocytes. Introduction of point mutations in the SRSF3-binding site or knockdown of SRSF3 expression in cells reduces 929^3434 splicing and E1^E4 production but activates other, minor 929^3465 and 929^3506 splicing. Knockdown of SRSF3 expression also enhances the expression of E2 and L1 mRNAs. An exonic splicing silencer (ESS) in the HPV18 nt 612 to 639 region was identified as being inhibitory to the 233^416 splicing of HPV18 E6E7 pre-mRNAs via binding to hnRNP A1, a well-characterized, abundantly and ubiquitously expressed RNA-binding protein. Introduction of point mutations into the hnRNP A1-binding site or knockdown of hnRNP A1 expression promoted 233^416 splicing and reduced E6 expression. These data provide the first evidence that the alternative RNA splicing of HPV18 pre-mRNAs is subject to regulation by viral RNA cis elements and host trans-acting splicing factors. IMPORTANCEExpression of HPV18 genes is regulated by alternative RNA splicing of viral polycistronic pre-mRNAs to produce a repertoire of viral early and late transcripts. RNA cis elements and trans-acting factors contributing to HPV18 alternative RNA splicing have been discovered in this study for the first time. The identified ESS at the E7 open reading frame (ORF) prevents HPV18 233^416 splicing in the E6 ORF through interaction with a host splicing factor, hnRNP A1, and regulates E6 and E7 expression of the early E6E7 polycistronic pre-mRNA. The identified ESE at the E1^E4 ORF promotes HPV18 929^3434 splicing of both viral early and late pre-mRNAs and E1^E4 production through interaction with SRSF3. This study provides important observations on how alternative RNA splicing of HPV18 pre-mRNAs is subject to regulation by viral RNA cis elements and host splicing factors and offers potential therapeutic targets to overcome HPV-related cancer.H igh-risk human papillomavirus (HPV) is associated with more than 95% of cervical cancer, 40 to 90% of anogenital cancer, and 10 to 60% of oropharyngeal cancer with geographic variation (1). Two major polycistronic pre-mRNAs, early and late pre-mRNAs, are transcribed from the high-risk HPV genome. Alternative RNA splicing of the HPV polycistronic pre-mRNAs plays a crucial role in regu...

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“…Additionally, SRSF2 regulates the splicing of the viral factors Tat (17)(18)(19)(20) and Rev (21), which are necessary for efficient HIV-1 replication. In human papillomavirus 16 (HPV16), SRSF2 positively regulated the expression and stability of E6E7 RNAs (22). In this report we reveal that the host splicing factor SRSF2 facilitates HSV-1 replication by regulating HSV-1 ICP0, infected cell polypeptide 27 (ICP27), and thymidine kinase (TK) expression.…”

mentioning

confidence: 75%

Serine/Arginine-rich Splicing Factor 2 Modulates Herpes Simplex Virus Type 1 Replication via Regulating Viral Gene Transcriptional Activity and Pre-mRNA Splicing

Wang

Liu

Lu³

et al. 2016

Journal of Biological Chemistry

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Edited by Joel GottesfeldOnce it enters the host cell, herpes simplex virus type 1 (HSV-1) recruits a series of host cell factors to facilitate its life cycle. Here, we demonstrate that serine/arginine-rich splicing factor 2 (SRSF2), which is an important component of the splicing speckle, mediates HSV-1 replication by regulating viral gene expression at the transcriptional and posttranscriptional levels. Our results indicate that SRSF2 functions as a transcriptional activator by directly binding to infected cell polypeptide 0 (ICP0), infected cell polypeptide 27 (ICP27), and thymidine kinase promoters. Moreover, SRSF2 participates in ICP0 pre-mRNA splicing by recognizing binding sites in ICP0 exon 3. These findings provide insight into the functions of SRSF2 in HSV-1 replication and gene expression.Herpes simplex virus type 1 (HSV-1) is a human ␣ herpesvirus that is associated with orofacial and genital herpes infections and is related to herpes encephalitis (1). The HSV-1 genome encodes Ͼ80 genes that are transcribed by RNA polymerase II (RNAP II) 3 (2). Of these viral genes, infected cell polypeptide 0 (ICP0) plays vital roles in facilitating the HSV-1 life cycle. In HSV-1-infected cells, ICP0 prevents the antiviral response triggered by dsDNA by degrading IFI16 (3), PML, and SP100 (4). Additionally, ICP0 inhibits host IRF3 nuclear signaling to prevent the interferon production-mediated antiviral response of the infected cells (5). ICP0 enables efficient viral replication by redistributing host CCND3 to ND10 bodies, which function as precursors of replication compartments (6).ICP0 also participates in HSV-1 reactivation. In the HSV-1 genome, ICP0 dissociates HDAC1 and HDAC2 from the HDAC-RCOR1-REST-KDM1A complex to make the viral DNA accessible for transcription factor binding (7). After infection, HSV-1 uses a series of host cell factors to facilitate its life cycle. Host cell factor 1, which is a cellular transcriptional coactivator, plays a central role in initiating the expression of viral immediate early (IE) genes by interacting with numerous host cell transcription factors, such as virion protein 16 (8) and early growth response protein 1, a protein that mediates IE gene expression by binding to the key regulatory elements near the HSV-1 IE genes (9). Moreover, the DNA methyltransferase DNMT3A has been reported to promote HSV-1 replication by associating with the viral capsid protein VP26 (10).Serine/arginine-rich splicing factor 2 (SRSF2 or SC35), which is a specific well known serine/arginine-rich (SR) protein family member, is well known as a mediator of genome stability, pre-mRNA splicing, mRNA nuclear export, and translational control (11-15). SRSF2 contains an RNA recognition motif for RNA binding and a domain rich in arginine and serine residues (RS domain) that facilitates its interaction with other SR splicing factors (13).To date several studies have investigated the roles of SRSF2 in viral infection. In HIV-1 infection, SRSF2 was reported to modulate viral replication by negatively regulatin...

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Human Papillomavirus 16 Oncoprotein Expression Is Controlled by the Cellular Splicing Factor SRSF2 (SC35)

Cited by 48 publications

References 54 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

Serine/Arginine-Rich Splicing Factor 3 and Heterogeneous Nuclear Ribonucleoprotein A1 Regulate Alternative RNA Splicing and Gene Expression of Human Papillomavirus 18 through Two Functionally Distinguishable cis Elements

Serine/Arginine-rich Splicing Factor 2 Modulates Herpes Simplex Virus Type 1 Replication via Regulating Viral Gene Transcriptional Activity and Pre-mRNA Splicing

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