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

doi:10.1128/JVI.00965-16

. 2016 Sep 29;90(20):9138-52.

doi: 10.1128/JVI.00965-16. Print 2016 Oct 15.

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

Masahiko Ajiro¹, Shuang Tang¹, John Doorbar², Zhi-Ming Zheng³

Affiliations

¹ Tumor Virus RNA Biology Section, Gene Regulation and Chromosome Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA.
² Division of Virology, Department of Pathology, University of Cambridge, Cambridge, UK.
³ Tumor Virus RNA Biology Section, Gene Regulation and Chromosome Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA zhengt@exchange.nih.gov.

PMID: 27489271
PMCID: PMC5044842
DOI: 10.1128/JVI.00965-16

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

Masahiko Ajiro et al. J Virol. 2016.

. 2016 Sep 29;90(20):9138-52.

doi: 10.1128/JVI.00965-16. Print 2016 Oct 15.

Authors

Masahiko Ajiro¹, Shuang Tang¹, John Doorbar², Zhi-Ming Zheng³

Affiliations

¹ Tumor Virus RNA Biology Section, Gene Regulation and Chromosome Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA.
² Division of Virology, Department of Pathology, University of Cambridge, Cambridge, UK.
³ Tumor Virus RNA Biology Section, Gene Regulation and Chromosome Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA zhengt@exchange.nih.gov.

PMID: 27489271
PMCID: PMC5044842
DOI: 10.1128/JVI.00965-16

Abstract

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 pre-mRNAs 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.

Importance: Expression 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.

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Figures

**FIG 1**
Updated transcription map of HPV18. Early (P_55/102) and late (P₈₁₁) promoters, early (pA_E at nt 4235) and late (pA_L at nt 7278) polyadenylation signals, and cleavage sites (Cs4270 and Cs7299/7307) are indicated in the linearized diagram of the HPV18 genome. Other, minor promoters, P_498/520/586 and P_{1193/1202/1207}, identified both in productive HPV18 infection (24) and in U2OS cells transfected with an HPV18 plasmid (25), are also shown. The promoter P_3036/3385, identified by *in vitro* transcription and chloramphenicol acetyltransferase (CAT) assays in HeLa cells (87) and in U2OS cells transfected with an HPV18 plasmid (25) but not confirmed in natural HPV18 infection, is represented by a dashed arrow. The numbers are the nucleotide positions in the reference HPV18 genome. LCR, long control region. The individual ORFs are shown above the linearized HPV18 genome, along with various RNA splicing isoforms below. The transcription map originated from the Zheng laboratory (24) and has been updated to include less abundant RNA isoforms from two recent publications (25, 26), with additional support from the current study. Exons (thick lines) and introns (thin lines) are illustrated for each RNA species derived from alternative promoter usage and alternative RNA splicing, with splice site positions numbered by nucleotide positions in the virus genome. The coding potentials for HPV18 viral proteins are shown on the right of each transcript. #, mRNAs reported only in transiently transfected U2OS cells (25) but not in HPV18-infected keratinocytes (24, 26).

**FIG 2**
Construction of the *in vitro* splicing system for the major HPV18 alternative splicing sites. (A) Diagrams of the pre-mRNAs tested for *in vitro* splicing assays. A U1 binding motif of 11 nt (gray boxes) was attached to the 3′ ends of pre-mRNAs 2, 4, 6, and 8 to enhance *in vitro* splicing. Pre-mRNAs 3 to 8 have a truncated intron ∼350 nt in size for *in vitro* splicing assays. (B) Splicing gels from *in vitro* splicing assays. The splicing reactions were performed by incubating each ³²P-labeled HPV18 pre-mRNA in panel A with HeLa nuclear extract at 30°C for 0, 1, and 2 h, and the splicing products were resolved on a 6% denaturing PAGE gel. The identities of unspliced pre-mRNA (a) and individual spliced products (b, b′, b″, and c) are indicated. The splicing efficiency (% spliced) was calculated from the splicing gels as described previously (32).

**FIG 3**
Identification of an ESE in the regulation of nt 929^3434 splicing of HPV18 pre-mRNAs. (A to C) Mapping of an ESE in regulation of *in vitro* splicing of HPV18 RNAs. HPV18 pre-mRNAs with successive truncations of the RNA 3′ end (A) were ³²P labeled and incubated with HeLa nuclear extract at 30°C for the indicated times (B and C). The splicing products were resolved on a 6% denaturing PAGE gel. The identities of unspliced pre-mRNAs (a) and spliced products (b, b′, c, d, and e) on the splicing gels are indicated. (D and E) Enhancement of *dsx* pre-mRNA splicing by the identified HPV18 ESE. *dsx* pre-mRNAs 1 to 7 with a fragmented ESE ∼30 nt in size from the HPV18 nt 3520 to 3635 region at their 3′ ends (D) were evaluated for their *in vitro* splicing activities (E). (AAG)₈ and a Py3 element (4) served as positive and negative controls, respectively. Details are shown in panels B and C.

**FIG 4**
Efficient *in vitro* RNA splicing requires an HPV18 ESE to interact with SRSF3. (A) The identified ESE 3520 to 3550 region in the HPV18 genome contains putative binding sites for SRSF3 (shaded boxes) and SRSF1 (open boxes). The RNA oligonucleotides derived from this region with a wild-type (18ESE wt) or mutant (18ESE mt-1, -2, and -3) sequence (mutated nucleotides are underlined) were used for RNA pulldown assays (34). (B) 18ESE wt binds SRSF3 only. RNA pulldown assays were performed by mixing individual 5′-biotin-conjugated RNAs with HeLa extract. The pulldown products were blotted by using anti-SRSF1, anti-SRSF3, and a mAb104 antibody that recognizes phosphorylated SR proteins. (C and D) *In vitro* RNA splicing of *dsx* pre-mRNAs requires interaction of the ESE and SRSF3. Six versions of the HPV18 ESE (C) were examined in *dsx* exon 3 and 4 pre-mRNAs for their splicing activities in a 2-h splicing reaction. The splicing efficiency (% spliced) was calculated from the splicing gel (32). The identities of spliced products are shown on the right.

**FIG 5**
SRSF3 promotes HPV18 929^3434 splicing for E1^E4 expression. (A) Diagram of HPV18 minigenes (pMA99 and pMA92) used for 929^3434 splicing. Plasmid pMA99 has a wt ESE containing two SRSF3-binding sites, and pMA92 has mutant ESE lacking SRSF3-binding sites, as shown in Fig. 4A. Both minigenes have a truncated intron of 339 nt and are under the control of a cytomegalovirus (CMV) immediate-early promoter (P_{CMV IE}) and a simian virus 40 (SV40) polyadenylation signal (pA_SV40) for their expression in mammalian cells. F1 and R1 are forward and reverse primers used for RT-PCR. The dots in the ESE sequence represent nucleotides without mutations. (B) Knockdown of SRSF3 expression in HEK293 cells or disruption of SRSF3-binding sites in HPV18 ESE significantly reduces the 929^3434 splicing of HPV18 minigene RNA in HEK293 cells. Total RNA from HEK293 cells transfected twice with si-NS or si-SRSF3 for 96 h (at an interval of 48 h) and once with the indicated HPV18 minigene for 24 h was used for RT-PCR, with GAPDH (glyceraldehyde-3-phosphate dehydrogenase) serving as a loading control. (C to F) Knockdown of SRSF3 expression in HEK293 cells reduces E1^E4 splicing (929^3434 splicing) and E1^E4 protein production but activates selection of other weak 3′ splice sites downstream of the major 3434 3′ splice site. Plasmid pMA35, an expanded version of pMA99, contains an E1^E4 ORF (C) and was used to evaluate the effect of SRSF3 knockdown on E1^E4 splicing and protein expression (D to F). Total RNA and protein from HEK293 cells with or without SRSF3 knockdown and pMA35 transfection as described above were separately prepared. The RNA samples were used for RT-PCR (D) with the primer pair F1 and R2 (indicated in panel C), and the protein samples were blotted for the E1^E4 protein by using an anti-HPV18 E1^E4 antibody (F). GAPDH RNA served as an internal loading control for RT-PCR (D), and β-actin served as a sample loading control for Western blotting (F). RT-PCR products 1, 2, and 3 (D) were gel purified, cloned, and sequenced and represent the respective products of 929^3434, 929^3465, and 929^3506 splicing (E). (D) The asterisk indicates a heterogeneous double-stranded DNA band with one strand from the 929^3434 products hybridized with another strand from the 929^3465 or 929^3605 product during PCR annealing (Fig. 6). RT− indicates no reverse transcriptase in RT-PCR.

**FIG 6**
Formation of heteroduplex DNA molecules containing a single-stranded loop from two RT-PCR products. (A) Agarose gel profile of the heteroduplex molecules. The gel-purified RT-PCR products from 929^3434 (lanes 2, 6, 10, and 14) and 929^3465 (lanes 3 and 7) or 929^3506 (lanes 11 and 15) splicing were mixed (lanes 4, 8, 12, and 16), heated at 100°C for 5 min (lanes 8 and 16), and annealed at 25°C for 1 h and then at 4°C for 1 h before loading onto an agarose gel for electrophoresis. The individual products or their mixtures without heating and annealing (lanes 2 to 4 and 10 to 12) served as controls. The band (lanes 8 and 16) appearing above the nt 929^3434 product after heating and annealing of the mixed products is the heteroduplex molecules containing single-stranded loops confirmable by TA cloning and sequencing. Lanes 1, 5, 9, and 13 are 100-bp DNA ladders. (B) Schematic of the RT-PCR products and their heteroduplex. The primer pair used for amplification is shown on the right. The identity of the mRNA from which the product was derived is shown on the left alongside the expected size of the product.

**FIG 7**
Knockdown of SRSF3 expression in keratinocytes reduces 929^3434 splicing but activates alternative splicing of other, weak 3′ splice sites and L1 expression during HPV18 infection. (A) Diagram showing HPV18 late pre-mRNA with major alternative splice sites. HPV18 ORFs (E1^E4, E2, and L1) are shown at the top, with the primers used in RT-PCR indicated by arrows (F1, F2, R2, R3, and R4) below the pre-mRNA. (B) Knockdown of SRSF3 activates alternative RNA splicing of HPV18 pre-mRNAs in HFK18 cells containing an episomal HPV18 genome, an HPV18-immortalized keratinocyte line derived from primary foreskin keratinocytes. Total RNA isolated from HFK18 cells transfected three times with si-NS or si-SRSF3, with an interval between transfections of 48 h, was used for RT-PCR, and the spliced RNA products from 929^3434, 929^3465, 929^3506, E2, and L1 were detected with a primer set indicated in each gel panel. *, a heterogeneous double-stranded DNA band as described in the legend to Fig. 5D. GAPDH RNA served as an internal loading control for RT-PCR. (C) SRSF3 knockdown appears to induce the expression of involucrin, a keratinocyte differentiation marker. HFK18 cells were cultured in growth media containing a low (0.17 mM) or high (2.5 mM) concentration of Ca²⁺ and were examined by Western blotting for involucrin as a differentiation marker. β-Actin served as a loading control. To test the SRSF3 knockdown effect, HFK18 cells grown in low-Ca²⁺ (0.17 mM) medium were transfected twice with si-SRSF3 or si-NS for 96 h, at an interval of 48 h, and maintained in low- or high-Ca²⁺ culture medium for a total of 4 days. Involucrin and β-actin were then blotted.

**FIG 8**
Identification of an ESS in regulation of HPV18 233^416 splicing. (A) Diagrams of pre-mRNAs 1 to 8 with successive exon 2 extensions. Each pre-mRNA's 3′ end was attached to a U1 binding motif (11 nt) (gray boxes) to enhance its splicing efficiency (20, 32). The numbers are the nucleotide positions in the virus genome. (B) Splicing gels from *in vitro* splicing assays. The splicing reactions were performed by incubating each ³²P-labeled HPV18 pre-mRNA in panel A with HeLa nuclear extract at 30°C for 2 h, and the splicing products were resolved on a 6% denaturing PAGE gel. The identities of unspliced pre-mRNAs and individual spliced products are indicated on the left. The splicing efficiency (% spliced) was calculated from the splicing gel as described (32).

**FIG 9**
Binding of hnRNP A1 to the identified ESS is responsible for regulation of HPV18 233^416 splicing. (A) RNA sequences of the identified ESS and its mutations. Predicted binding sites for hnRNP F and hnRNP A1 are indicated by open and shaded boxes, respectively. The wt and mt (mt-1, mt-2, and mt-3) RNA oligonucleotides (mutated nucleotides are underlined) were used for RNA pulldown assays. (B) HPV18 ESE binds hnRNP A1. RNA pulldown assays were performed by mixing each RNA oligonucleotide in panel A with HeLa cell extract. The pulldown products were then blotted using anti-hnRNP A1, anti-hnRNP F, and mAb104 antibodies. (C) Diagram of HPV18 minigenes bearing a wt (pMA31) or mt (pMA77) ESS for HPV18 233^416 splicing assays in HEK293 cells. Both minigenes containing intact E6 and E7 ORFs are under the control of a CMV IE promoter (P_{CMV IE}) and an SV40 polyadenylation signal (pA_SV40). The horizontal arrows represent primers (F3, F4, and R5) used in RT-PCR. The numbers below the diagram are the nucleotide positions in the virus genome. The wt and mt ESS sequences are detailed below the diagram. (D and E) hnRNP A1 regulates HPV18 233^416 splicing through the ESS. HEK293 cells without (D) or with (E) hnRNP A1 knockdown were transfected with pMA31 or pMA77 for 24 h before extraction of total RNA for RT-PCR analysis using the primer pair F3 plus R5 (D) or F4 plus R5 (E). GAPDH RNA served as a loading control. (F) Diagram of HPV18 E6E7 polycistronic pre-mRNA derived from the viral early promoter P_55/102 and polyadenylated at a viral early pA site (pA_E). The numbers on the E6 and E7 ORFs and the diagram are the nucleotide positions in the virus genome. F4 and R5 are two primers used for RT-PCR analysis. (G) Knockdown of hnRNP A1 in HeLa cells promotes HPV18 233^416 splicing and reduces E6 intron retention. Total RNA from HeLa cells transfected twice with si-NS or si-SRSF3 for 96 h, at an interval of 48 h, was examined by RT-PCR. GAPDH RNA served as a loading control. (H) The knockdown efficiency of hnRNP A1 in HEK293 or HeLa cells was evaluated by Western blotting. β-Actin served as a loading control. RT− in panels D and E and G and H indicates no reverse transcriptase in RT-PCR.

**FIG 10**
Regulation of HPV18 pre-mRNA splicing by an hnRNP A1-dependent ESS and an SRSF3-dependent ESE. HPV18 early pre-mRNA (top) and late pre-mRNA (bottom) are regulated by multiple alternative splicing events. The identified ESS in the nt 612 to 639 region binds hnRNP A1 to reduce nt 233^416 splicing of HPV18 E6E7 pre-mRNA for the production of E6 mRNA. The identified ESE in the nt 3520 to 3550 region binds SRSF3 to promote HPV18 929^3434 splicing for expression of viral early genes and E1^E4. Loss of SRSF3 binding to this region or reduction of SRSF3 expression activates selection of other, minor 3′ splice sites upstream or downstream of the nt 3434 3′ splice site.

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References

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1. Zheng ZM, He P, Baker CC. 1996. Selection of the bovine papillomavirus type 1 nucleotide 3225 3′ splice site is regulated through an exonic splicing enhancer and its juxtaposed exonic splicing suppressor. J Virol 70:4691–4699. - PMC - PubMed
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[1] de Martel C, Ferlay J, Franceschi S, Vignat J, Bray F, Forman D, Plummer M. 2012. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol 13:607–615. doi:10.1016/S1470-2045(12)70137-7. - DOI - PubMed

[2] de Martel C, Ferlay J, Franceschi S, Vignat J, Bray F, Forman D, Plummer M. 2012. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol 13:607–615. doi:10.1016/S1470-2045(12)70137-7. - DOI - PubMed

[3] Ajiro M, Zheng ZM. 2014. Oncogenes and RNA splicing of human tumor viruses. Emerg Microbes Infect 3:e63. doi:10.1038/emi.2014.62. - DOI - PMC - PubMed

[4] Ajiro M, Zheng ZM. 2014. Oncogenes and RNA splicing of human tumor viruses. Emerg Microbes Infect 3:e63. doi:10.1038/emi.2014.62. - DOI - PMC - PubMed

[5] Zheng ZM, Baker CC. 2006. Papillomavirus genome structure, expression, and post-transcriptional regulation. Front Biosci 11:2286–2302. doi:10.2741/1971. - DOI - PMC - PubMed

[6] Zheng ZM, Baker CC. 2006. Papillomavirus genome structure, expression, and post-transcriptional regulation. Front Biosci 11:2286–2302. doi:10.2741/1971. - DOI - PMC - PubMed

[7] Zheng ZM, He P, Baker CC. 1996. Selection of the bovine papillomavirus type 1 nucleotide 3225 3′ splice site is regulated through an exonic splicing enhancer and its juxtaposed exonic splicing suppressor. J Virol 70:4691–4699. - PMC - PubMed

[8] Zheng ZM, He P, Baker CC. 1996. Selection of the bovine papillomavirus type 1 nucleotide 3225 3′ splice site is regulated through an exonic splicing enhancer and its juxtaposed exonic splicing suppressor. J Virol 70:4691–4699. - PMC - PubMed

[9] Zheng ZM, He PJ, Baker CC. 1997. Structural, functional, and protein binding analyses of bovine papillomavirus type 1 exonic splicing enhancers. J Virol 71:9096–9107. - PMC - PubMed

[10] Zheng ZM, He PJ, Baker CC. 1997. Structural, functional, and protein binding analyses of bovine papillomavirus type 1 exonic splicing enhancers. J Virol 71:9096–9107. - PMC - PubMed

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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

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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

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