References
Ablasser, A., & Hur, S. (2020). Regulation of cGAS- and RLR-mediated immunity to nucleic acids. Nature Immunology 21, 17-29, doi: 10.1038/s41590-019-0556-1.h https://doi.org/10.1038/s41590-019-0556-1
Akira, S., Uematsu, S., & Takeuchi, O. (2006). Pathogen recognition and innate immunity. Cell 124, 783-801, doi: 10.1016/j.cell.2006.02.015.
Albertini, S., Lo Cigno, I., Calati, F., De Andrea, M., Borgogna, C., Dell’Oste, V., Landolfo, S., & Gariglio, M. (2018). HPV18 persistence impairs basal and DNA ligand-mediated IFN-β and IFN-λ1production through transcriptional repression of multiple downstream effectors of pattern recognition receptor signaling. Journal of Immunology 200, 2076-2089, doi: 10.4049/jimmunol.1701536.
Ban, J., Lee, N.R., Lee, N.J., Lee, J.K., Quan, F.S., & Inn, K.S. (2018). Human respiratory syncytial virus NS1 targets TRIM25 to suppress RIG-I ubiquitination and subsequent RIG-I -mediated antiviral signaling. Viruses 10, 716, doi:10.3390/v10120716.
Banoth, B., & Cassel, S. (2018). Mitochondria in innate immune signaling. Translation Research 202, 52-68, doi: 10.1016/j.trsl.2018.07.014.
Borzacchiello, G., Russo, V., Gentile, F., Roperto, F., Venuti A., Nitsch, L., Campo, M.S., & Roperto, S. (2006). Bovine papillomavirus E5 oncoprotein binds to the activated form of the platelet-derived growth factor beta receptor in naturally occurring bovine urinary bladder tumours. Oncogene 25, 1251-1260, doi: 10.1038/sj.onc.1209152.
Campo, M.S., Jarrett, W.F.H., Barron, R.J., O’Neil, B.W., & Smith, K.T. (1992). Association of bovine papillomavirus type 2 and bracken fern with bladder cancer in cattle. Cancer Research 52, 6898–6904.
Chen, T., Wang, D., Xie, T., & Xu, L.G. (2018). Sec13 is a positive regulator of VISA-mediated antiviral signaling. Virus Genes 54, 514-526, doi: 10.1007/s11262-018-1581-0.
Chiang, C., Pauli, E.K., Biryukov, J., Feister, K.F., Meng, M., White, E.A., Münger, K., Howley, P.M., Meyers, C., & Gack, M.U. (2018). The human papillomavirus E6 oncoprotein targets USP15 and TRIM25 to suppress RIG-I-mediated innate immune signaling. Journal of Virology 92, e01737-17, doi: 10.1128/JVI.01737-17
Chow, K.T., Gale, M., & Loo, Y.M. (2018). RIG-I and other RNA sensors in antiviral immunity. Annual Review of Immunology 36, 667-694, doi: 10.1146/annurev-immunol-042617-053309.
Darlympe, N.A., Cimica, V., Mackow, E.R. (2015). Dengue virus NS proteins inhibit RIG-I/MAVS signaling by blocking TBK1/IRF3 phosphorylation: Dengue virus serotype 1 NS4A is a unique interferon-regulating virulence determinant. mBio 6(3), e00553-15, doi: 10.1128/mBio.00553-15.
DiMaio, D., & Petti, L. (2013). The E5 proteins. Virology 445, 99–114, doi: 10.1016/j.virol.2013.05.006.
Ding, Z., Fang, L., Jing, H., Zeng, S., Wang, D., Liu, L., Zhang, H., Luo, R., Chen, H., & Xiao, S. (2014). Porcine epidemic diarrhea virus nucleocapsid protein antagonizes beta interferon production sequestering the interaction between IRF3 and TBK1. Journal of Virology 88, 8936-8945, doi:10.1128/JVI.00700-14.
Doorbar, J., (2006). Molecular biology of human papillomavirus infection in cervical cancer. Clinical Science (London) 110, 525-541, doi: 10.1042/CS20050369.
Esser-Nobis, K., Hatfield, L.D., & Gale, M. Jr. (2020). Spatiotemporal dynamics of innate immune signaling via RIG-I-like receptors. Proceedings of the National Academy of Sciences, U.S.A. 117, 15778-15788, doi: 10.1073/pnas.1921861117.
Fang, R., Jiang, Q., Zhou, X., Wang, C., Guan, Y., Tao, J., Xi, J., Feng, J.M., & Jiang, Z. (2017). MAVS activates TBK1 and IKKε through TRAFS in NEMO dependent and independent manner. PLoS Pathogens 13: e1006720, doi: 10.1371/journal.ppat.1006720.
Fitzgerald, K.A., McWirther, S.M., Faia, K.L., Rowe, D.C., Latz, E., Golenbock, D.T., Coyle, A.J., Liao, S.M., & Maniatis, T. (2003). IKKε and TBK1 are essential components of the IRF3 signaling pathway. Nature Immunology 4, 491-496, doi:10.1038/ni921.
Gack, M.U., Shin, Y.C., Joo, C.H., Urano, T., Liang, C., Sun, L., Takeuchi, O., Akira, S., Chen, Z., Inoue, S., & Jung, J.E. (2007). TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature 446, 916-921, doi:10.1038/nature05732.
Goubau, D., Deddouche, S., & Reis e Sousa, C. (2013). Cytosolic sensing of viruses. Immunity 38, 855-869, doi: 10.1016/j.immuni.2013.05.007.
Groves, I.J., & Coleman, N. (2015). Pathogenesis of human papillomavirus-associated mucosal disease. Journal of Pathology 235, 527-538, doi: 10.1002/path.4496.
Hayman, T.J., Hsu, A.C., Kolesnik, T.B., Dagley, L.F., Willemsen, J., Tate, M.D., Baker, P.J., Kershaw, N.J., Kedzierski, L., Webb, A.I., Wark, P.A., Kedzierska, K., Masters, S.L., Belz, G.T., Binder, M., Hansbro, P.M., Nicola, N.A., & Nicholson, S.E. (2019). RIPLET, and not TRIM25, is required for endogenous RIG-I-dependent antiviral responses. Immunology & Cell Biology 97, 840-852, doi: 10.1111/imcb.12284.
Herdman, M.T., Pett, M.R., Roberts, I., Alazawi, W.O.F., Teschendorff, A.E., Zhang, X.Y., Stanley, M.A., & Coleman, N. (2006). Interferon-β treatment of cervical keratinocytes naturally infected with human papillomavirus 16 episomes promotes rapid reduction in episome members and emergence of latent integrants. Carcinogenesis 27, 2341-2353, doi:10.1093/carcin/bgl172.
Hong, S., & Laimins, L.A. (2017). Manipulation of the innate immune response by human papillomaviruses. Virus Research 231, 34-40, doi:10.1093/carcin/bgl172.
Hou, F., Sun, L., Zheng, H., Skaug, B., Jiang, O.X., & Chen, Z.L. (2011). MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response. Cell 146, 448-461, doi:10.1016/j.cell.2011.06.041.
Huo, H., Wang, Y., Wang, D., Chen, X., Zhao, L. & Chen, H. (2019). Duck RIG-I restricts duck enteritis virus infection. Veterinary Microbiology 230, 78-85, doi: 10.1016/j.vetmic.2019.01.014.
IARC Monographs on the Evaluation of Carcinogenic Risk to Humans, 2007.Human papillomavirus (Vol. 90 , p. 47). (World Health Organization, editor), Lyon, France: WHO Press.
Koiliopoulos, M.G., Lethier,M., van der Veen, A., G., Haubrich, K., Hennig, J., Kowalinski, E., Stevens, R.V., Martin, S.R., Reis e Sousa, C., Cusak, S., & Rittinger, K. (2018). Molecular mechanism of influenza A NS1-mediated TRIM25 recognition and inhibition. Nature Communications 9, 1820, doi: 10.1038/s41467-018-04214-8.
Loo, Y.M., & Gale, M. (2011). Immune signaling by RIG-I-like receptors. Immunity 34, 680-692, doi:10.1016/j.immuni.2011.05.003.
Onoguchi, K., Yoneyama, M., Takemura, A., Akira, S., Taniguchi, T., Namiki, H., & Fujita, T. (2007). Viral infections activate types I and III interferon genes through a common mechanism. The Journal of Biological Chemistry 282, 7576-7581, doi: 10.1074/jbc.M608618200.
Oshiumi, H., (2020). Recent advances and contradictions in the study of the individual roles of ubiquitin ligases that regulate Rig-I-like receptor-mediated antiviral innate immune responses. Frontiers in Immunology 11, 1296, doi: 10.3389/fimmu.2020.01296.
Oshiumi, H., Miyashita, M., Matsumoto, M., & Seya, T. (2013). A distinct role of Riplet-mediated K63-linked polyubiquitination of the RIG-I repressor domain in human antiviral innate immune responses. PLoS Pathogens 9(8), e1003533, doi: 10.1371/journal.ppat.1003533.
Reiser, J., Hurst, J., Voges, M., Krauss, P., Münch, P., Iftner, T., & Stubenrauch, F. (2011). High-risk human papillomaviruses repress constitutive kappa interferon transcription via E6 to prevent pathogen recognition receptor and antiviral-gene expression. Journal of Virology 85, 11372-11380, doi: 10.1128/JVI.05279-11.
Roperto, S., Borzacchiello, G., Brun, R., Leonardi, L., Maiolino, P., Martano, M., Paciello, O., Papparella., S., Restucci, B., Russo, V., Salvatore, G., Urraro, C., & Roperto, F. (2010a). A review of bovine urothelial tumours and tumour-like lesions of the urinary bladder. Journal of Comparative Pathology 142, 95-108, doi: 10.1016/j.jcpa.2009.08.156.
Roperto, S., De Tullio, R., Raso, C., Stifanese, R., Russo, V., Gaspari, M., Borzacchiello, G., Averna, M., Paciello, O., Cuda, G., & Roperto, F. (2010b). Calpain3 is expressed in a proteolitically form in papillomavirus-associated urothelial tumors of the urinary bladder in cattle. PLoS One 5(4), e10299, doi: 10.1371/journal.pone.0010299.
Roperto, S., Russo, V., Esposito, I., Ceccarelli, D.M., Paciello, O., Avallone, L., Capparelli, R., & Roperto, F. (2014). Mincle, an innate immune receptor, is expressed in urothelial cancer cells of papillomavirus-associated urothelial tumors of cattle. PLoS One 10(10), e0141624, doi: 10.1371/journal.pone.0141624.
Roperto, S., Russo, V., Ozkul, A., Sepici-Dincel, A., Maiolino, P., Borzacchiello, G., Marcus, I., Esposito, I., Riccardi, M.G., & Roperto, F. (2013). Bovine papillomavirus type 2 infects the urinary bladder of water buffalo (Bubalus bubalis) and plays a crucial role in bubaline urothelial carcinogenesis. Journal of General Virology 94, 403-408, doi: 10.1099/vir.0.047662-0.
Seth, R.B., Sun, L., Ea, C.K., & Chen, Z.J. (2005). Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kB and IRF3. Cell 122, 669-682, doi:10.1016/j.cell.2005.08.012.
Shi, Y., Yuan, B., Zhu, W., Zhang, R., Li, L., Hao, X., Chen, S., & Hou, F. (2017). Ube2D3 and Ube2N are essential for RIG-I-mediated MAVS aggregation in antiviral innate immunity. Nature Communications 8, 15138, doi: 10.1038/ncomms15138.
Stone, A.E.L., Green, R., Wilkins, C., Hermann, E.A., & Gale, M. Jr. (2019). RIG-I-like receptors direct inflammatory macrophage polarization against West Nile virus infection. Nature Communications 10, 3649, doi:10.1038/s41467-019-11250-5
Suprynowicz, F.A., Campo, M.S., & Schlegel, R. (2006). Biological activities of papillomavirus E5 proteins. In: Papillomavirus Research – from natural history to vaccine and beyond, Campo, M. S., Ed., Caister Academic Press, Norfolk, England, pp 97-113.
Takeuchi, O., & Akira, S. (2010). Pattern recognition receptors and inflammation. Cell 140, 805-820, doi:10.1016/j.cell.2010.01.022.
Turek, L.P., Byrne, J.C., Lowy, D.R., Dvoretzky, I., Friedman, R.M., & Howley, P.M. (1982). Interferon induces morphologic reversion with elimination of extrachromosomal viral genomes in bovine papillomavirus-transformed mouse cells. Proceedings of the National Academy of Sciences, U.S.A. 79, 7914-7918, doi: 10.1073/pnas.79.24.7914.
Wang, H.T., & Hur, S. (2020). Substrate recognition by TRIM and TRIM-like proteins in innate immunity. Seminars in Cell and Developmental Biology, doi:10.1016/j.semcdb.2020.09.013
Westrich, J.A., Warren, C.J., & Pyeon, D. (2017). Evasion of host immune defenses by human papillomavirus. Virus Research 231, 21-33, doi: 10.1016/j.virusres.2016.11.023.
Yamashita-Kawanishi, N., Ito, S., Ishiyama, D., Chambers, J.K., Uchida, K., Kasuya, F., & Haga, T. (2020). Characterization of bovine papillomavirus 28 (BPV28) and a novel genotype BPV29 associated with vulval papillomas in cattle. Veterinary Microbiology 250, 108879, doi 10.1016/j.vetmic.2020.108879.
Yoneyama, M., Onomoto, K., Jogi, M., Akaboshi, T., & Fujita, T. (2015). Viral RNA detection by RIG-I-like receptors. Current Opinion in Immunology 32, 48-53, doi:10.1016/j.coi.2014.12.012
Zhang, X., Zhu, Z., Wang, C., Yang, F., Cao, W., Li, P., Du, X., Zhao, F., Liu, X., & Zheng, H. (2020). Foot-and-mouth disease virus 3B protein interacts with pattern recognition receptor RIG-I-mediated immune signaling and inhibit host antiviral response. Journal of Immunology 205, 2207-2221, doi: 10.4049/jimmunol.1901333.
Zhu, W., Li, J., Zhang, R., Cai, Y., Wang, C., Qi, S., Chen, S., Liang, X., Qi, N., & Hou, F. (2019). TRAF3IP3 mediates the recruitment of TRAF3 to MAVS for antiviral innate immunity. The EMBO Journal 38, e102075, doi: 10.15252/embj.2019102075.
Figure legends
Fig. 1. (A) Western blot analysis of E5 protein from three healthy and four representative diseased bladder mucosa samples. Results of Western blot analysis are representative of three independent experiments.
Fig. 2. Immunoprecipitation assay using anti-TRIM25 and anti-Riplet antibodies in healthy and pathological bladder samples. Western blot analysis revealed that TRIM25 only interacted with E5 protein. Panels A and B show representative data from three independent experiments
Fig. 3. (A) Western blot analysis of total Riplet protein in healthy and diseased bladder samples. (B) Densitometric analysis of total Riplet protein relative to the β-actin protein level. Panels A and B show representative data from three independent experiments.
Fig. 4. (A) Western blot analysis of TRIM25 in 10 normal and 15 diseased bladder samples. (B) Densitometric analysis was performed by comparing the protein expression level of TRIM25 with that of β-actin. TRIM25 protein level was significantly lower in pathological bladder mucosa samples than in healthy samples. The calculations were based on two independent determinations. The values are expressed as a percentage of the average values for the healthy samples (**p ≤ 0.01).
Fig. 5: (A) Western blot analysis of RIG-1 and MDA5 in normal and pathological bovine urinary bladder samples. (B) Densitometric analysis was performed by comparing the protein expression levels of total RIG-1 and MDA5 with those of β-actin. RIG-1 and MDA5 protein levels were significantly reduced in the infected mucosa samples compared with the healthy samples (* p ≤ 0.05).
Fig. 6. Real-time RT-PCR analysis of RIG-I and MDA5 mRNA levels in 10 healthy and 15 pathological bladder samples. RIG-I and MDA mRNA expressions were significantly reduced in diseased bladder samples compared with normal bladder samples (*** p ≤ 0.001). Data are expressed as the mean ± S.E.M. of three independent experiments performed in triplicate.
Fig. 7. Real-time RT-PCR of TRIM25 mRNA levels in 10 healthy and 15 pathological bladder samples. Data are expressed as the mean ± S.E.M. of independent experiments performed in triplicate.
Fig. 8. Immunoprecipitation using an anti-MAVS antibody in healthy and diseased bladder samples. Western blot analysis revealed that MAVS interacted with RIG-I, MDA5, TRIM25, phosphorylated TBK1 (pTBK1), phosphorylated IRF3 (pIRF3) and Sec13. Immunoprecipitation panel shows representative data from three independent experiments.
Fig. 9. (A) Western blot analysis of total Sec13 protein performed in healthy and pathological bladder mucosa samples. (B) Densitometric analysis was performed by comparing the protein expression level of total Sec13 with that of β-actin. Sec13 protein level was significantly reduced in the pathological bladder mucosa samples (** p ≤ 0.01). Panels A and B show representative data from three independent experiments.
Fig. 10. (A) Western blot analysis of IRF3 and TBK1 in normal and diseased bovine bladders. (B) Densitometric analysis was performed by comparing the protein expression levels of total TBK1 and IRF3 with those of β-actin. IRF3 and TBK1 protein levels were significantly reduced in the neoplastic bladder mucosa samples compared with healthy samples (*** p≤0.001 and * p ≤ 0.05, respectively). Panels A and B show representative data from three independent experiments.
Fig. 11. (A) Western blot analysis of phosphorylated TBK1 (pTBK1) in the total lysate in healthy and pathological samples. (B) Densitometric analysis of pTBK1 protein was performed relative with β-actin protein levels. The calculations were based on three independent determinations. The values for the latter are expressed as percentages of the average values for the healthy samples (* p≤0.05). Panels A and B show representative data from three independent experiments.
Supplemental Fig S1. (A) Real-time RT-PCR analysis of BPV-2 and BPV-13 E5 mRNA expression in healthy and pathological bovine bladder samples. Lane MW: DNA molecular weight marker (100-base pair (bp) ladder); lanes 2 – 4: three representative diseased bladder samples; lane 5: healthy bladder sample; lane C: no template control (no cDNA added). (B) The amplicon sequences showed 100% identity with BPV-2 E5 and BPV-13 E5 sequences deposited in GenBank (Accession numbers: M20219.1 and JQ798171.1, respectively). Electrophoretic representative data were obtained from three independent experiments.
Supplemental Fig S2. (A) TRIM25 cDNA amplification by PCR in normal and pathological bovine urinary bladder samples compared with β-actin. Lane 1: molecular weight marker (DNA marker ladder); lanes 2-5: four representative diseased bladder samples; lanes 6-9: healthy bladder samples; in the last channel: negative control (RNA without reverse transcriptase subjected to PCR analysis). (B) The lower part of the figure shows the alignment of the sequences, which revealed 100% identity with bovine TRIM25 transcript sequences deposited in GenBank (Bos taurus tripartite motif containing 25 (TRIM25), mRNA: NM_001100336.1).
Supplemental Fig S3. (A) RIG-I and MDA5 cDNA amplification by PCR in normal and neoplastic bovine urinary bladder samples compared with β-actin. Lane 1: molecular weight marker (DNA marker ladder); lanes 2-5: four representative diseased bladder samples; lanes 6-9: healthy bladder samples; in the last channel: negative control (RNA without reverse transcriptase subjected to PCR analysis).
(B) The lower part of the figure shows the alignment of the sequences, which revealed 100% identity with bovine RIG-I and MDA5 transcript sequences deposited in GenBank (Bos taurus DExD/H-box helicase 58 (DDX58), transcript variant X1, mRNA: XM_002689480.6; Bos taurus interferon induced with helicase C domain 1 (IFH1), mRNA: XM_010802053.2).