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Learning noncoding RNA biology from viruses

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Abstract

Insights into interactions between viral factors and the cellular machinery usually lead to discoveries concerning host cell biology. Thus, the gene expression field has historically relied on viral model systems to discover mechanisms underlying different cellular processes. In recent years, the functional characterization of the small nuclear noncoding RNAs expressed by the oncogenic Herpesvirus saimiri, called HSURs, resulted in the discovery of two mechanisms for the regulation of gene expression. HSUR1 and HSUR2 associate with host microRNAs, which are small noncoding RNAs that broadly regulate gene expression by binding to messenger RNAs. HSUR1 provided the first example of a process known as target-directed miRNA degradation that operates in cells to regulate miRNA populations. HSUR2 functions as a miRNA adaptor, uncovering an entirely new, indirect mechanism by which miRNAs can inhibit mRNA function. Here, I review the path that led to these discoveries and their implications and postulate new exciting questions about the functions of these fascinating viral noncoding RNAs.

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References

  • Ameres SL, Horwich MD, Hung JH, Xu J, Ghildiyal M, Weng Z, Zamore PD (2010) Target RNA-directed trimming and tailing of small silencing RNAs. Science 328:1534–1539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aw JG, Shen Y, Wilm A, Sun M, Lim XN, Boon KL, Tapsin S, Chan YS, Tan CP, Sim AY, Zhang T, Susanto TT, Fu Z, Nagarajan N, Wan Y (2016) In vivo mapping of eukaryotic RNA interactomes reveals principles of higher-order organization and regulation. Mol Cell 62:603–617

    Article  CAS  PubMed  Google Scholar 

  • Bartel DP (2018) Metazoan MicroRNAs. Cell 173:20–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bitetti A, Mallory AC, Golini E, Carrieri C, Carreno Gutierrez H, Perlas E, Perez-Rico YA, Tocchini-Valentini GP, Enright AJ, Norton WHJ, Mandillo S, O’Carroll D, Shkumatava A (2018) MicroRNA degradation by a conserved target RNA regulates animal behavior. Nat Struct Mol Biol 25:244–251

    Article  CAS  PubMed  Google Scholar 

  • Bonci D, Coppola V, Musumeci M, Addario A, Giuffrida R, Memeo L, D’Urso L, Pagliuca A, Biffoni M, Labbaye C, Bartucci M, Muto G, Peschle C, De Maria R (2008) The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities. Nat Med 14:1271–1277

    Article  CAS  PubMed  Google Scholar 

  • Brummer A, Hausser J (2014) MicroRNA binding sites in the coding region of mRNAs: extending the repertoire of post-transcriptional gene regulation. BioEssays 36:617–626

    Article  PubMed  CAS  Google Scholar 

  • Buck AH, Perot J, Chisholm MA, Kumar DS, Tuddenham L, Cognat V, Marcinowski L, Dolken L, Pfeffer S (2010) Post-transcriptional regulation of miR-27 in murine cytomegalovirus infection. RNA 16:307–315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burgering BM, Kops GJ (2002) Cell cycle and death control: long live Forkheads. Trends Biochem Sci 27:352–360

    Article  CAS  PubMed  Google Scholar 

  • Cabrera-Ortega AA, Feinberg D, Liang Y, Rossa C Jr, Graves DT (2017) The Role of Forkhead Box 1 (FOXO1) in the Immune System: Dendritic Cells, T Cells, B Cells, and Hematopoietic Stem Cells. Crit Rev Immunol 37:1–13

    Article  PubMed  PubMed Central  Google Scholar 

  • Cai Z, Cao C, Ji L, Ye R, Wang D, Xia C, Wang S, Du Z, Hu N, Yu X, Chen J, Wang L, Yang X, He S, Xue Y (2020) RIC-seq for global in situ profiling of RNA-RNA spatial interactions. Nature 582:432–437

    Article  CAS  PubMed  Google Scholar 

  • Cazalla D, Xie M, Steitz JA (2011) A primate herpesvirus uses the integrator complex to generate viral MicroRNAs. Mol Cell 43:982–992

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cazalla D, Yario T, Steitz JA (2010) Down-regulation of a host microRNA by a Herpesvirus saimiri noncoding RNA. Science 328:1563–1566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chandradoss SD, Schirle NT, Szczepaniak M, MacRae IJ, Joo C (2015) A dynamic search process underlies MicroRNA targeting. Cell 162:96–107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen CZ, Li L, Lodish HF, Bartel DP (2004) MicroRNAs modulate hematopoietic lineage differentiation. Science 303:83–86

    Article  CAS  PubMed  Google Scholar 

  • Chi SW, Zang JB, Mele A, Darnell RB (2009) Argonaute HITS-CLIP decodes microRNA-mRNA interaction maps. Nature 460:479–486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chipman LB, Pasquinelli AE (2019) miRNA targeting: growing beyond the seed. Trends Genet 35:215–222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chou CS, Geck P, Medveczky MM, Hernandez OM, Medveczky PG (1995) Induction of a herpesvirus saimiri small RNA AU binding factor (AUBF70) activity and lymphokine mRNAs by T cell mitogens. Arch Virol 140:415–435

    Article  CAS  PubMed  Google Scholar 

  • Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, Wojcik SE, Aqeilan RI, Zupo S, Dono M, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM (2005) miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A 102:13944–13949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cook HL, Mischo HE, Steitz JA (2004) The Herpesvirus saimiri small nuclear RNAs recruit AU-rich element-binding proteins but do not alter host AU-rich element-containing mRNA levels in virally transformed T cells. Mol Cell Biol 24:4522–4533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de la Mata M, Gaidatzis D, Vitanescu M, Stadler MB, Wentzel C, Scheiffele P, Filipowicz W, Grosshans H (2015) Potent degradation of neuronal miRNAs induced by highly complementary targets. EMBO Rep 16:500–511

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ensser A, Fleckenstein B (2005) T-cell transformation and oncogenesis by gamma2-herpesviruses. Adv Cancer Res 93:91–128

    Article  CAS  PubMed  Google Scholar 

  • Fan XC, Myer VE, Steitz JA (1997) AU-rich elements target small nuclear RNAs as well as mRNAs for rapid degradation. Genes Dev 11:2557–2568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fang Z, Rajewsky N (2011) The impact of miRNA target sites in coding sequences and in 3’UTRs. PLoS One 6:e18067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gorbea C, Mosbruger T, Cazalla D (2017) A viral Sm-class RNA base-pairs with mRNAs and recruits microRNAs to inhibit apoptosis. Nature 550:275–279

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gorbea C, Mosbruger T, Nix DA, Cazalla D (2019) Viral miRNA adaptor differentially recruits miRNAs to target mRNAs through alternative base-pairing. eLife 8:e50530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gorski SA, Vogel J, Doudna JA (2017) RNA-based recognition and targeting: sowing the seeds of specificity. Nat Rev Mol Cell Biol 18:215–228

    Article  CAS  PubMed  Google Scholar 

  • Guo YE, Riley KJ, Iwasaki A, Steitz JA (2014) Alternative capture of noncoding RNAs or protein-coding genes by herpesviruses to alter host T cell function. Mol Cell 54:67–79

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hafner M, Landthaler M, Burger L, Khorshid M, Hausser J, Berninger P, Rothballer A, Ascano M Jr, Jungkamp AC, Munschauer M, Ulrich A, Wardle GS, Dewell S, Zavolan M, Tuschl T (2010) Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell 141:129–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han J, LaVigne CA, Jones BT, Zhang H, Gillett F, Mendell JT (2020) A ubiquitin ligase mediates target-directed microRNA decay independently of tailing and trimming. Science 370:eabc9546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J (2013) Natural RNA circles function as efficient microRNA sponges. Nature 495:384–388

    Article  CAS  PubMed  Google Scholar 

  • He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, Powers S, Cordon-Cardo C, Lowe SW, Hannon GJ, Hammond SM (2005) A microRNA polycistron as a potential human oncogene. Nature 435:828–833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson DR, Jondal M (1981a) Herpesvirus ateles and herpesvirus saimiri transform marmoset T cells into continuously proliferating cell lines that can mediate natural killer cell-like cytotoxicity. Proc Natl Acad Sci U S A 78:6391–6395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson DR, Jondal M (1981b) Herpesvirus-transformed cytotoxic T-cell lines. Nature 291:81–83

    Article  CAS  PubMed  Google Scholar 

  • Kitamura T (2013) The role of FOXO1 in beta-cell failure and type 2 diabetes mellitus. Nat Rev Endocrinol 9:615–623

    Article  CAS  PubMed  Google Scholar 

  • Kiyotaki M, Desrosiers RC, Letvin NL (1986) Herpesvirus saimiri strain 11 immortalizes a restricted marmoset T8 lymphocyte subpopulation in vitro. J Exp Med 164:926–931

    Article  CAS  PubMed  Google Scholar 

  • Kleaveland B, Shi CY, Stefano J, Bartel DP (2018) A network of noncoding regulatory RNAs acts in the mammalian brain. Cell 174:350-362 e317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kohtz JD, Jamison SF, Will CL, Zuo P, Luhrmann R, Garcia-Blanco MA, Manley JL (1994) Protein-protein interactions and 5’-splice-site recognition in mammalian mRNA precursors. Nature 368:119–124

    Article  CAS  PubMed  Google Scholar 

  • Kramer NJ, Wang WL, Reyes EY, Kumar B, Chen CC, Ramakrishna C, Cantin EM, Vonderfecht SL, Taganov KD, Chau N, Boldin MP (2015) Altered lymphopoiesis and immunodeficiency in miR-142 null mice. Blood 125:3720–3730

    Article  CAS  PubMed  Google Scholar 

  • Kudla G, Granneman S, Hahn D, Beggs JD, Tollervey D (2011) Cross-linking, ligation, and sequencing of hybrids reveals RNA-RNA interactions in yeast. Proc Natl Acad Sci U S A 108:10010–10015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kunne T, Swarts DC, Brouns SJ (2014) Planting the seed: target recognition of short guide RNAs. Trends Microbiol 22:74–83

    Article  PubMed  CAS  Google Scholar 

  • Lavigueur A, La Branche H, Kornblihtt AR, Chabot B (1993) A splicing enhancer in the human fibronectin alternate ED1 exon interacts with SR proteins and stimulates U2 snRNP binding. Genes Dev 7:2405–2417

    Article  CAS  PubMed  Google Scholar 

  • Lee FCY, Ule J (2018) Advances in CLIP technologies for studies of protein-RNA interactions. Mol Cell 69:354–369

    Article  CAS  PubMed  Google Scholar 

  • Lee S, Song J, Kim S, Kim J, Hong Y, Kim Y, Kim D, Baek D, Ahn K (2013) Selective degradation of host MicroRNAs by an intergenic HCMV noncoding RNA accelerates virus production. Cell Host Microbe 13:678–690

    Article  CAS  PubMed  Google Scholar 

  • Lee SI, Murthy SC, Trimble JJ, Desrosiers RC, Steitz JA (1988) Four novel U RNAs are encoded by a herpesvirus. Cell 54:599–607

    Article  CAS  PubMed  Google Scholar 

  • Libri V, Helwak A, Miesen P, Santhakumar D, Borger JG, Kudla G, Grey F, Tollervey D, Buck AH (2012) Murine cytomegalovirus encodes a miR-27 inhibitor disguised as a target. Proc Natl Acad Sci U S A 109:279–284

    Article  CAS  PubMed  Google Scholar 

  • Liu J, Carmell MA, Rivas FV, Marsden CG, Thomson JM, Song JJ, Hammond SM, Joshua-Tor L, Hannon GJ (2004) Argonaute2 is the catalytic engine of mammalian RNAi. Science 305:1437–1441

    Article  CAS  PubMed  Google Scholar 

  • Liu Q, Fu H, Sun F, Zhang H, Tie Y, Zhu J, Xing R, Sun Z, Zheng X (2008) miR-16 family induces cell cycle arrest by regulating multiple cell cycle genes. Nucleic Acids Res 36:5391–5404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu X, Li X, He Q, Gao J, Gao Y, Liu B, Liu F (2013) miR-142-3p regulates the formation and differentiation of hematopoietic stem cells in vertebrates. Cell Res 23:1356–1368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu Z, Zhang QC, Lee B, Flynn RA, Smith MA, Robinson JT, Davidovich C, Gooding AR, Goodrich KJ, Mattick JS, Mesirov JP, Cech TR, Chang HY (2016) RNA duplex map in living cells reveals higher-order transcriptome structure. Cell 165:1267–1279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marcinowski L, Tanguy M, Krmpotic A, Radle B, Lisnic VJ, Tuddenham L, Chane-Woon-Ming B, Ruzsics Z, Erhard F, Benkartek C, Babic M, Zimmer R, Trgovcich J, Koszinowski UH, Jonjic S, Pfeffer S, Dolken L (2012) Degradation of cellular mir-27 by a novel, highly abundant viral transcript is important for efficient virus replication in vivo. PLoS Pathog 8:e1002510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maroney PA, Yu Y, Fisher J, Nilsen TW (2006) Evidence that microRNAs are associated with translating messenger RNAs in human cells. Nat Struct Mol Biol 13:1102–1107

    Article  CAS  PubMed  Google Scholar 

  • Meister G, Landthaler M, Patkaniowska A, Dorsett Y, Teng G, Tuschl T (2004) Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. Mol Cell 15:185–197

    Article  CAS  PubMed  Google Scholar 

  • Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M, Loewer A, Ziebold U, Landthaler M, Kocks C, le Noble F, Rajewsky N (2013) Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495:333–338

    Article  CAS  PubMed  Google Scholar 

  • Murthy S, Kamine J, Desrosiers RC (1986) Viral-encoded small RNAs in herpes virus saimiri induced tumors. EMBO J 5:1625–1632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murthy SC, Trimble JJ, Desrosiers RC (1989) Deletion mutants of herpesvirus saimiri define an open reading frame necessary for transformation. J Virol 63:3307–3314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Myer VE, Lee SI, Steitz JA (1992) Viral small nuclear ribonucleoproteins bind a protein implicated in messenger RNA destabilization. Proc Natl Acad Sci U S A 89:1296–1300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nguyen TC, Cao X, Yu P, Xiao S, Lu J, Biase FH, Sridhar B, Huang N, Zhang K, Zhong S (2016) Mapping RNA-RNA interactome and RNA structure in vivo by MARIO. Nat Commun 7:12023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nimmo R, Ciau-Uitz A, Ruiz-Herguido C, Soneji S, Bigas A, Patient R, Enver T (2013) MiR-142-3p controls the specification of definitive hemangioblasts during ontogeny. Dev Cell 26:237–249

    Article  CAS  PubMed  Google Scholar 

  • Nottrott S, Simard MJ, Richter JD (2006) Human let-7a miRNA blocks protein production on actively translating polyribosomes. Nat Struct Mol Biol 13:1108–1114

    Article  CAS  PubMed  Google Scholar 

  • Oliveira AC, Bovolenta LA, Nachtigall PG, Herkenhoff ME, Lemke N, Pinhal D (2017) Combining results from distinct MicroRNA target prediction tools enhances the performance of analyses. Front Genet 8:59

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pawlica P, Moss WN, Steitz JA (2016) Host miRNA degradation by Herpesvirus saimiri small nuclear RNA requires an unstructured interacting region. RNA 22:1181–1189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pawlica P, Sheu-Gruttadauria J, MacRae IJ, Steitz JA (2019) How complementary targets expose the microRNA 3’ end for tailing and trimming during target-directed microRNA degradation. Cold Spring Harb Symp Quant Biol 84:179–183

    Article  PubMed  Google Scholar 

  • Rissland OS, Hong SJ, Bartel DP (2011) MicroRNA destabilization enables dynamic regulation of the miR-16 family in response to cell-cycle changes. Mol Cell 43:993–1004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roscigno RF, Garcia-Blanco MA (1995) SR proteins escort the U4/U6.U5 tri-snRNP to the spliceosome. RNA 1:692–706

    CAS  PubMed  PubMed Central  Google Scholar 

  • Salomon WE, Jolly SM, Moore MJ, Zamore PD, Serebrov V (2015) Single-molecule imaging reveals that argonaute reshapes the binding properties of its nucleic acid guides. Cell 162:84–95

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schirle NT, Sheu-Gruttadauria J, MacRae IJ (2014) Structural basis for microRNA targeting. Science 346:608–613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schnall-Levin M, Zhao Y, Perrimon N, Berger B (2010) Conserved microRNA targeting in Drosophila is as widespread in coding regions as in 3’UTRs. Proc Natl Acad Sci U S A 107:15751–15756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sharma E, Sterne-Weiler T, O’Hanlon D, Blencowe BJ (2016) Global Mapping of Human RNA-RNA Interactions. Mol Cell 62:618–626

    Article  CAS  PubMed  Google Scholar 

  • Sheu-Gruttadauria J, Pawlica P, Klum SM, Wang S, Yario TA, Schirle Oakdale NT, Steitz JA, MacRae IJ (2019) Structural basis for target-directed MicroRNA degradation. Mol Cell 75:1243-1255 e1247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi CY, Kingston ER, Kleaveland B, Lin DH, Stubna MW, Bartel DP (2020) The ZSWIM8 ubiquitin ligase mediates target-directed microRNA degradation. Science 370:eabc9359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun Q, Mayeda A, Hampson RK, Krainer AR, Rottman FM (1993) General splicing factor SF2/ASF promotes alternative splicing by binding to an exonic splicing enhancer. Genes Dev 7:2598–2608

    Article  CAS  PubMed  Google Scholar 

  • Tarn WY, Steitz JA (1995) Modulation of 5’ splice site choice in pre-messenger RNA by two distinct steps. Proc Natl Acad Sci U S A 92:2504–2508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tian M, Maniatis T (1993) A splicing enhancer complex controls alternative splicing of doublesex pre-mRNA. Cell 74:105–114

    Article  CAS  PubMed  Google Scholar 

  • Ulitsky I, Shkumatava A, Jan CH, Sive H, Bartel DP (2011) Conserved function of lincRNAs in vertebrate embryonic development despite rapid sequence evolution. Cell 147:1537–1550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xie J, Ameres SL, Friedline R, Hung JH, Zhang Y, Xie Q, Zhong L, Su Q, He R, Li M, Li H, Mu X, Zhang H, Broderick JA, Kim JK, Weng Z, Flotte TR, Zamore PD, Gao G (2012) Long-term, efficient inhibition of microRNA function in mice using rAAV vectors. Nat Methods 9:403–409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamamura S, Imai-Sumida M, Tanaka Y, Dahiya R (2018) Interaction and cross-talk between non-coding RNAs. Cell Mol Life Sci 75:467–484

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, Tang N, Hadden TJ, Rishi AK (2011) Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta 1813:1978–1986

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

I would like to thank Carlos Gorbea for critical commentary and discussions.

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  1. Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA

    Demián Cazalla

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Cazalla, D. Learning noncoding RNA biology from viruses. Mamm Genome 33, 412–420 (2022). https://doi.org/10.1007/s00335-021-09915-y

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