In addition to mature mRNAs, splicing of pol II transcripts generates numerous other RNAs including circular RNAs (circRNAs). circRNAs are a group of transcripts generated by non-sequential back splicing or forward splicing of exons, introns or a combination of both from a donor to an acceptor target. This forms covalently closed RNA molecule i.e. without free 5’ end caps or 3’ Poly (A) tails thereby making them more stable than their linear counterparts. Though they are recognized as part of non-coding RNAs, long noncoding precisely; evidence of translations has been reported from these molecules. circRNAs are considered emerging new members of the gene regulatory family. These circRNAs have several potential modes of action, some of which serve as microRNAs sponges shown in Table 1, protein binding RNAs, cellular transports, transcriptional regulators and modulating immune system. Viral circRNAs may evade immune recognition by many proposed mechanisms. These include undergoing slicing by host splicing machinery, being single stranded lacking free 5’ and 3’ ends, having miRNA sponge function, convenient regulatory functions which include initiating lytic replication, etc. Pattern of expression of these circRNAs differs from healthy individuals to different stages of viral infectious diseases. Thus, their use as potential biomarkers for diagnostics and future therapeutics targets have been proposed, especially with regards to viral infections that seem impossible for the human immune system to totally eliminate like the Epstein- Barr viral infection. So, this review summarizes the functions and implications of circRNAs regarding antiviral immunity.
References
[1]
Yan, N. and Chen, Z.J. (2012) Intrinsic Antiviral Immunity. Nature Immunology, 13, 214-222. https://doi.org/10.1038/ni.2229
[2]
Van Rij, R.P. and Andino, R. (2008) The Complex Interactions of Viruses and the RNAi Machinery: A Driving Force in Viral Evolution. In: Domingo, E., Parrish, C.R. and Holland, J.J., Eds., Origin and Evolution of Viruses, Elsevier, Amsterdam, 161-181. https://doi.org/10.1016/B978-0-12-374153-0.00007-2
[3]
Liang, D. and Wilusz, J.E. (2014) Short Intronic Repeat Sequences Facilitate Circular RNA Production. Genes & Development, 28, 2233-2247. https://doi.org/10.1101/gad.251926.114
Memczak, S., et al. (2013) Circular RNAs Are a Large Class of Animal RNAs with Regulatory Potency. Nature, 495, 333-338. https://doi.org/10.1038/nature11928
[6]
Jeck, W.R. and Sharpless, N.E. (2014) Detecting and Characterizing Circular RNAs. Nature Biotechnology, 32, 453-461. https://doi.org/10.1038/nbt.2890
[7]
Toptan, T., et al. (2018) Circular DNA Tumor Viruses Make Circular RNAs. Proceedings of the National Academy of Sciences of the United States of America, 115, E8737-E8745. https://doi.org/10.1073/pnas.1811728115
[8]
Ungerleider, N., et al. (2018) The Epstein Barr Virus circRNAome. PLOS Pathogens, 14, e1007206. https://doi.org/10.1371/journal.ppat.1007206
[9]
Jin, X., Feng, C.Y., Xiang, Z., Chen, Y.P. and Li, Y.M. (2016) CircRNA Expression Pattern and circRNA-miRNA-mRNA Network in the Pathogenesis of Nonalcoholic Steatohepatitis. Oncotarget, 7, 66455-66467. https://doi.org/10.18632/oncotarget.12186
[10]
Barrett, S.P. and Salzman, J. (2016) Circular RNAs: Analysis, Expression and Potential Functions. Development, 143, 1838-1847. https://doi.org/10.1242/dev.128074
[11]
Lyu, D. and Huang, S. (2016) The Emerging Role and Clinical Implication of Human Exonic Circular RNA. RNA Biology, 14, 1000-1006.
[12]
Salzman, J., Gawad, C., Wang, P.L., Lacayo, N. and Brown, P.O. (2012) Circular RNAs Are the Predominant Transcript Isoform from Hundreds of Human Genes in Diverse Cell Types. PLoS ONE, 7, e30733. https://doi.org/10.1371/journal.pone.0030733
[13]
Hsiao, K.Y., Sun, H.S. and Tsai, S.J. (2017) Circular RNA—New Member of Noncoding RNA with Novel Functions. Experimental Biology and Medicine, 242, 1136-1141. https://doi.org/10.1177/1535370217708978
[14]
Sanger, H.L., Klotz, G., Riesner, D., Gross, H.J. and Kleinschmidt, A.K. (1976) Viroids Are Single-Stranded Covalently Closed Circular RNA Molecules Existing as Highly Base-Paired Rod-Like Structures. Proceedings of the National Academy of Sciences of the United States of America, 73, 3852-3856. https://doi.org/10.1073/pnas.73.11.3852
[15]
Guo, J.U., Agarwal, V., Guo, H. and Bartel, D.P. (2014) Expanded Identification and Characterization of Mammalian Circular RNAs. Genome Biology, 15, 409. https://doi.org/10.1186/PREACCEPT-1176565312639289
[16]
Jeck, W.R., et al. (2013) Circular RNAs Are Abundant, Conserved, and Associated with ALU Repeats. RNA, 19, 141-157. https://doi.org/10.1261/rna.035667.112
[17]
Salzman, J., Chen, R.E., Olsen, M.N., Wang, P.L. and Brown, P.O. (2013) Cell-Type Specific Features of Circular RNA Expression. PLOS Genetics, 9, e1003777. https://doi.org/10.1371/journal.pgen.1003777
[18]
Carninci, P., et al. (2005) The Transcriptional Landscape of the Mammalian Genome. Science, 309, 1559-1563. https://doi.org/10.1126/science.1112014
[19]
Wang, M., et al. (2017) Circular RNAs: A Novel Type of Non-Coding RNA and Their Potential Implications in Antiviral Immunity. International Journal of Biological Sciences, 13, 1497-1506. https://doi.org/10.7150/ijbs.22531
[20]
Zhao, Z.J. and Shen, J. (2017) Circular RNA Participates in the Carcinogenesis and the Malignant Behavior of Cancer. RNA Biology, 14, 514-521. https://doi.org/10.1080/15476286.2015.1122162
[21]
Pamudurti, N.R., et al. (2017) Translation of CircRNAs. Molecular Cell, 66, 9-21e7. https://doi.org/10.1016/j.molcel.2017.02.021
[22]
Sand, M., et al. (2016) Circular RNA Expression in Cutaneous Squamous Cell Carcinoma. Journal of Dermatological Science, 83, 210-218. https://doi.org/10.1016/j.jdermsci.2016.05.012
[23]
Miao, R., et al. (2017) Microarray Expression Profile of Circular RNAs in Chronic Thromboembolic Pulmonary Hypertension. Medicine, 96, e7354. https://doi.org/10.1097/MD.0000000000007354
[24]
Jiang, G., et al. (2017) Relationships of Circular RNA with Diabetes and Depression. Scientific Reports, 7, Article No. 7285. https://doi.org/10.1038/s41598-017-07931-0
[25]
Haque, S. and Harries, L.W. (2017) Circular RNAs (circRNAs) in Health and Disease. Genes (Basel), 8, 353. https://doi.org/10.3390/genes8120353
[26]
Chen, Y.G., et al. (2017) Sensing Self and Foreign Circular RNAs by Intron Identity. Molecular Cell, 67, 228-238e5. https://doi.org/10.1016/j.molcel.2017.05.022
[27]
Li, X., et al. (2017) Coordinated circRNA Biogenesis and Function with NF90/NF110 in Viral Infection. Molecular Cell, 67, 214-227e7. https://doi.org/10.1016/j.molcel.2017.05.023
[28]
Zhang, X., et al. (2017) Circular RNA Alterations Are Involved in Resistance to Avian Leukosis Virus Subgroup-J-Induced Tumor Formation in Chickens. Oncotarget, 8, 34961-34970. https://doi.org/10.18632/oncotarget.16442
[29]
Legnini, I., et al. (2017) Circ-ZNF609 Is a Circular RNA That Can Be Translated and Functions in Myogenesis. Molecular Cell, 66, 22-37.e9. https://doi.org/10.1016/j.molcel.2017.02.017
[30]
Yang, Y., et al. (2017) Extensive Translation of Circular RNAs Driven by N6-Methyladenosine. Cell Research, 27, 626-641. https://doi.org/10.1038/cr.2017.31
[31]
Wang, Y. and Wang, Z. (2015) Efficient Backsplicing Produces Translatable Circular mRNAs. RNA, 21, 172-179. https://doi.org/10.1261/rna.048272.114
[32]
Wei, C.M., Gershowitz, A. and Moss, B. (1975) Methylated Nucleotides Block 5’ Terminus of HeLa Cell Messenger RNA. Cell, 4, 379-386. https://doi.org/10.1016/0092-8674(75)90158-0
[33]
Li, S. and Mason, C.E. (2014) The Pivotal Regulatory Landscape of RNA Modifications. Annual Review of Genomics and Human Genetics, 15, 127-150. https://doi.org/10.1146/annurev-genom-090413-025405
[34]
Sun, C., Querol-Audi, J., Mortimer, S.A., et al. (2013) Two RNA-Binding Motifs in eIF3 Direct HCV IRES-Dependent Translation. Nucleic Acids Research, 41, 7512-7521. https://doi.org/10.1093/nar/gkt510
[35]
Meyer, K.D., Patil, D.P., Zhou, J., et al. (2015) 5’ UTR m(6)A Promotes Cap Independent Translation. Cell, 163, 999-1010. https://doi.org/10.1016/j.cell.2015.10.012
[36]
Liberman, N., Gandin, V., Svitkin, Y.V., et al. (2015) DAP5 Associates with eIF2beta and eIF4AI to Promote Internal Ribosome Entry Site Driven Translation. Nucleic Acids Research, 43, 3764-3775. https://doi.org/10.1093/nar/gkv205
[37]
Zhang, Y., et al. (2017) Circular RNAs: Emerging Cancer Biomarkers and Targets. Journal of Experimental & Clinical Cancer Research, 36, 152. https://doi.org/10.1186/s13046-017-0624-z
[38]
Peng, L., Yuan, X.Q. and Li, G.C. (2015) The Emerging Landscape of Circular RNA ciRS-7 in Cancer (Review). Oncology Reports, 33, 2669-2674. https://doi.org/10.3892/or.2015.3904
[39]
Hansen, T.B., Kjems, J. and Damgaard, C.K. (2013) Circular RNA and miR-7 in Cancer. Cancer Research, 73, 5609-5612. https://doi.org/10.1158/0008-5472.CAN-13-1568
[40]
Fischer, J.W. and Leung, A.K. (2017) CircRNAs: A Regulator of Cellular Stress. Critical Reviews in Biochemistry and Molecular Biology, 52, 220-233. https://doi.org/10.1080/10409238.2016.1276882
[41]
Du, W.W., et al. (2017) Foxo3 Circular RNA Promotes Cardiac Senescence by Modulating Multiple Factors Associated with Stress and Senescence Responses. European Heart Journal, 38, 1402-1412.
[42]
Zheng, Q., et al. (2016) Circular RNA Profiling Reveals an Abundant circHIPK3 That Regulates Cell Growth by Sponging Multiple miRNAs. Nature Communications, 7, Article No. 11215. https://doi.org/10.1038/ncomms11215
[43]
Wang, F., Nazarali, A.J. and Ji, S. (2016) Circular RNAs as Potential Biomarkers for Cancer Diagnosis and Therapy. American Journal of Cancer Research, 6, 1167-1176.
[44]
Abdelmohsen, K., et al. (2017) Identification of HuR Target Circular RNAs Uncovers Suppression of PABPN1 Translation by circPABPN1. RNA Biology, 14, 361-369. https://doi.org/10.1080/15476286.2017.1279788
[45]
Li, Z., et al. (2015) Exon Intron Circular RNAs Regulate Transcription in the Nucleus. Nature Structural & Molecular Biology, 22, 256-264. https://doi.org/10.1038/nsmb.2959
[46]
Ashwal-Fluss, R., Meyer, M., Pamudurti, N.R., Ivanov, A., Bartok, O. and Hanan, M. (2014) circRNA Biogenesis Competes with pre-mRNA Splicing. Molecular Cell, 56, 55-66. https://doi.org/10.1016/j.molcel.2014.08.019
[47]
Conn, V.M., et al. (2017) A circRNA from SEPALLATA3 Regulates Splicing of Its Cognate mRNA through R-Loop Formation. Nature Plants, 3, 17053. https://doi.org/10.1038/nplants.2017.53
[48]
Cadena, C. and Hur, S. (2017) Antiviral Immunity and Circular RNA: No End in Sight. Molecular Cell, 67, 163-164. https://doi.org/10.1016/j.molcel.2017.07.005
[49]
Sun, L., Liu, S. and Chen, Z.J. (2010) SnapShot: Pathways of Antiviral Innate Immunity. Cell, 140, 436e2. https://doi.org/10.1016/j.cell.2010.01.041
[50]
Kell, A.M. and Gale, M.J. (2015) RIG-I in RNA Virus Recognition. Virology, 479-480, 110-121. https://doi.org/10.1016/j.virol.2015.02.017
Ghosh, Z., Mallick, B. and Chakrabarti, J. (2009) Cellular versus Viral microRNAs in Host-Virus Interaction. Nucleic Acids Research, 37, 1035-1048. https://doi.org/10.1093/nar/gkn1004
[53]
Scaria, V., Hariharan, M., Maiti, S., Pillai, B. and Brahmachari, S.K. (2006) Host-Virus Interaction: A New Role for microRNAs. Retrovirology, 3, 1-9. https://doi.org/10.1186/1742-4690-3-68
[54]
Skalsky, R.L. and Cullen, B.R. (2010) Viruses, microRNAs, and Host Interactions. Annual Review of Microbiology, 64, 123-141. https://doi.org/10.1146/annurev.micro.112408.134243
[55]
Louten, J., Beach, M., Palermino, K., Weeks, M. and Holenstein, G. (2015) MicroRNAs Expressed during Viral Infection: Biomarker Potential and Therapeutic Considerations. Biomarker Insights, 10, 25-52. https://doi.org/10.4137/BMI.S29512
[56]
Cai, X., et al. (2006) Epstein-Barr Virus microRNAs Are Evolutionarily Conserved and Differentially Expressed. PLOS Pathogens, 2, e23. https://doi.org/10.1371/journal.ppat.0020023
[57]
Gartner, J.J., Sethupathy, P., Hatzigeorgiou, A.G. and Fraser, N.W. (2008) Anti Apoptotic Function of a microRNA Encoded by the HSV-1 Latency-Associated Transcript. Nature, 451, 600. https://doi.org/10.1038/nature06621
[58]
Sullivan, C.S., Grundhoff, A.T., Tevethia, S., Pipas, J.M. and Ganem, D. (2005) SV40-Encoded microRNAs Regulate Viral Gene Expression and Reduce Susceptibility to Cytotoxic T Cells. Nature, 435, 682-686. https://doi.org/10.1038/nature03576
[59]
Jung, Y.-J., Choi, H., Kim, H. and Lee, S.K. (2014) MicroRNA miR-BART20-5p Stabilizes Epstein-Barr Virus Latency by Directly Targeting BZLF1 and BRLF1. Journal of Virology, 88, 9027-9037. https://doi.org/10.1128/JVI.00721-14
[60]
Qiu, J., Smith, P., Leahy, L. and Thorley-Lawson, D.A. (2015) The Epstein-Barr Virus Encoded BART miRNAs Potentiate Tumor Growth in Vivo. PLOS Pathogens, 11, e1004561. https://doi.org/10.1371/journal.ppat.1004561
[61]
He, L., et al. (2017) Deep Circular RNA Sequencing Provides Insights into the Mechanism Underlying Grass Carp Reovirus Infection. International Journal of Molecular Sciences, 18, pii: E1977. https://doi.org/10.3390/ijms18091977
[62]
Chen, J., et al. (2017) Circular RNA Profile Identifies circPVT1 as a Proliferative Factor and Prognostic Marker in Gastric Cancer. Cancer Letters, 388, 208-219. https://doi.org/10.1016/j.canlet.2016.12.006
[63]
Suzuki, H. and Tsukahara, T.A. (2014) View of pre-mRNA Splicing from RNase R Resistant RNAs. International Journal of Molecular Sciences, 15, 9331-9342. https://doi.org/10.3390/ijms15069331
[64]
Lasda, E. and Parker, R. (2016) Circular RNA Co-Precipitate with Extracellular Vesicles: A Possible Mechanism for circRNA Clearance. PLoS ONE, 11, e0148407. https://doi.org/10.1371/journal.pone.0148407
[65]
Memczak, S., Papavasileiou, P., Peters, O. and Rajewsky, N. (2015) Identification and Characterization of Circular RNAs as a New Class of Putative Biomarkers in Human Blood. PLoS ONE, 10, e0141214. https://doi.org/10.1371/journal.pone.0141214
[66]
Bahn, J.H., et al. (2014) The Landscape of microRNA, Piwi-Interacting RNA, and Circular RNA in Human Saliva. Clinical Chemistry, 61, 221-230. https://doi.org/10.1373/clinchem.2014.230433
[67]
Shao, Y., et al. (2017) Global Circular RNA Expression Profile of Human Gastric Cancer and Its Clinical Significance. Cancer Medicine, 6, 1173-1180. https://doi.org/10.1002/cam4.1055
[68]
Li, Y., et al. (2015) Circular RNA Is Enriched and Stable in Exosomes: A Promising Biomarker for Cancer Diagnosis. Cell Research, 25, 981-984. https://doi.org/10.1038/cr.2015.82
[69]
Li, P., et al. (2015) Using Circular RNA as a Novel Type of Biomarker in the Screening of Gastric Cancer. Clinica Chimica Acta, 444, 132-136. https://doi.org/10.1016/j.cca.2015.02.018
[70]
Chen, S., Li, T., Zhao, Q., Xiao, B. and Guo, J. (2017) Using Circular RNA Hsa_Circ_0000190 as a New Biomarker in the Diagnosis of Gastric Cancer. Clinica Chimica Acta, 466, 167-171. https://doi.org/10.1016/j.cca.2017.01.025
[71]
Sun, Y.M., Lin, K.Y. and Chen, Y.Q. (2013) Diverse Functions of miR-125 Family in Different Cell Contexts. Journal of Hematology & Oncology, 6, 6. https://doi.org/10.1186/1756-8722-6-6
