Processing of virus‐derived cytoplasmic primary‐microRNAs

Focus Article

Jillian S. Shapiro

Published Online: May 28 2013

DOI: 10.1002/wrna.1169

Full article on Wiley Online Library: HTML PDF

Can't access this content? Tell your librarian.

MicoRNAs (miRNAs) are small noncoding RNAs that associate with Argonaute (AGO) family member proteins to mediate silencing of host mRNA transcripts. A number of DNA viruses and a single retrovirus exploit this pathway to generate their own miRNAs in an effort to self regulate or combat the host immune response to infection. While natural examples of viral miRNAs have been limited to nuclear viruses, manipulation of cytoplasmic‐restricted RNA virus genomes revealed the ability of these vectors to produce abundant levels of mature, functional miRNAs, exclusively within the cytoplasm. This novel processing mechanism is found to be dependent upon the ribonuclease (RNAse) III proteins Drosha and Dicer, while processing is able to proceed in the absence of the canonical dsRNA binding proteins DiGeorge syndrome critical region gene 8 (DGCR8), Tar RNA binding protein 2 (TRBP2), and protein kinase R activating protein (PACT). Processing of cytoplasmic restricted primary‐miRNA transcripts (c‐pri‐miRNAs) corresponds with virus‐induced redistribution of Drosha, implicating the formation of a noncanonical microprocessor. This review will discuss c‐pri‐miRNA processing, the mechanism of miRNA production, and the implications of a virus‐induced cytoplasmic microprocessor. WIREs RNA 2013, 4:463–471. doi: 10.1002/wrna.1169 This article is categorized under: RNA Processing > Processing of Small RNAs Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs

This WIREs title offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images

Small RNA pathways in insects and mammalians. In Drosophila melanogaster, virus‐derived dsRNA is cleaved by Dicer‐2 in to duplex RNAs, one strand of which mediates the targeting of pathogen RNA. In mammalians, miRNAs are produced in a stepwise fashion, via Drosha and Dicer, to produce a small RNA that mediates silencing of host transcripts.

[ Normal View | Magnified View ]

Proposed mechanism of c‐pri‐miRNA processing. (1) SINV infection leads to Drosha relocalization and the production of c‐pri‐miRNAs within the cytoplasm; (2) Drosha mediates the cytoplasmic cleavage of c‐pri‐miRNAs, releasing a pre‐miRNA that is (3) processed by Dicer. (4) One strand of the duplex is loaded into RISC where it (5) mediates post‐transcriptional silencing.

[ Normal View | Magnified View ]

References

Ebert, MS, Sharp, PA. Roles for microRNAs in conferring robustness to biological processes. Cell 2012, 149:515–524.
Lagos‐Quintana, M, Rauhut, R, Lendeckel, W, Tuschl, T. Identification of novel genes coding for small expressed RNAs. Science 2001, 294:853–858.
Lim, LP, Glasner, ME, Yekta, S, Burge, CB, Bartel, DP. Vertebrate microRNA genes. Science 2003, 299:1540.
Lee, Y, Kim, M, Han, J, Yeom, KH, Lee, S, Baek, SH, Kim, VN. MicroRNA genes are transcribed by RNA polymerase II. EMBO J 2004, 23:4051–4060.
Denli, AM, Tops, BB, Plasterk, RH, Ketting, RF, Hannon, GJ. Processing of primary microRNAs by the microprocessor complex. Nature 2004, 432:231–235.
Gregory, RI, Yan, KP, Amuthan, G, Chendrimada, T, Doratotaj, B, Cooch, N, Shiekhattar, R. The Microprocessor complex mediates the genesis of microRNAs. Nature 2004, 432:235–240.
Han, J, Lee, Y, Yeom, KH, Nam, JW, Heo, I, Rhee, JK, Sohn, SY, Cho, Y, Zhang, BT, Kim, VN. Molecular basis for the recognition of primary microRNAs by the Drosha‐DGCR8 complex. Cell 2006, 125:887–901.
Lund, E, Guttinger, S, Calado, A, Dahlberg, JE, Kutay, U. Nuclear export of microRNA precursors. Science 2004, 303:95–98.
Yi, R, Qin, Y, Macara, IG, Cullen, BR. Exportin‐5 mediates the nuclear export of pre‐microRNAs and short hairpin RNAs. Genes Dev 2003, 17:3011–3016.
Ketting, RF, Fischer, SE, Bernstein, E, Sijen, T, Hannon, GJ, Plasterk, RH. Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C. elegans. Genes Dev 2001, 15:2654–2659.
Bernstein, E, Caudy, AA, Hammond, SM, Hannon, GJ. Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 2001, 409:363–366.
Hutvagner, G, McLachlan, J, Pasquinelli, AE, Balint, E, Tuschl, T, Zamore, PD. A cellular function for the RNA‐interference enzyme Dicer in the maturation of the let‐7 small temporal RNA. Science 2001, 293:834–838.
Park, JE, Heo, I, Tian, Y, Simanshu, DK, Chang, H, Jee, D, Patel, DJ, Kim, VN. Dicer recognizes the 5′ end of RNA for efficient and accurate processing. Nature 2011, 475:201–205.
Lee, Y, Hur, I, Park, SY, Kim, YK, Suh, MR, Kim, VN. The role of PACT in the RNA silencing pathway. EMBO J 2006, 25:522–532.
Haase, AD, Jaskiewicz, L, Zhang, H, Laine, S, Sack, R, Gatignol, A, Filipowicz, W. TRBP, a regulator of cellular PKR and HIV‐1 virus expression, interacts with Dicer and functions in RNA silencing. EMBO Rep 2005, 6:961–967.
Chendrimada, TP, Gregory, RI, Kumaraswamy, E, Norman, J, Cooch, N, Nishikura, K, Shiekhattar, R. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature 2005, 436:740–744.
Khvorova, A, Reynolds, A, Jayasena, SD. Functional siRNAs and miRNAs exhibit strand bias. Cell 2003, 115:209–216.
Schwarz, DS, Hutvagner, G, Du, T, Xu, Z, Aronin, N, Zamore, PD. Asymmetry in the assembly of the RNAi enzyme complex. Cell 2003, 115:199–208.
Bazzini, AA, Lee, MT, Giraldez, AJ. Ribosome profiling shows that miR‐430 reduces translation before causing mRNA decay in Zebrafish. Science 2012, 336:233–237.
Djuranovic, S, Nahvi, A. Green R: miRNA‐mediated gene silencing by translational repression followed by mRNA deadenylation and decay. Science 2012, 336:237–240.
Guo, H, Ingolia, NT, Weissman, JS, Bartel, DP. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 2010, 466:835–840.
Zekri, L, Huntzinger, E, Heimstadt, S, Izaurralde, E. The silencing domain of GW182 interacts with PABPC1 to promote translational repression and degradation of microRNA targets and is required for target release. Mol Cell Biol 2009, 29:6220–6231.
Okamura, K, Hagen, JW, Duan, H, Tyler, DM, Lai, EC. The mirtron pathway generates microRNA‐class regulatory RNAs in Drosophila. Cell 2007, 130:89–100.
Ruby, JG, Jan, CH, Bartel, DP. Intronic microRNA precursors that bypass Drosha processing. Nature 2007, 448:83–86.
Babiarz, JE, Ruby, JG, Wang, Y, Bartel, DP, Blelloch, R. Mouse ES cells express endogenous shRNAs, siRNAs, and other Microprocessor‐independent, Dicer‐dependent small RNAs. Genes Dev 2008, 22:2773–2785.
Taft, RJ, Glazov, EA, Lassmann, T, Hayashizaki, Y, Carninci, P, Mattick, JS. Small RNAs derived from snoRNAs. RNA 2009, 15:1233–1240.
Glazov, EA, Cottee, PA, Barris, WC, Moore, RJ, Dalrymple, BP, Tizard, ML. A microRNA catalog of the developing chicken embryo identified by a deep sequencing approach. Genome Res 2008, 18:957–964.
Ender, C, Krek, A, Friedlander, MR, Beitzinger, M, Weinmann, L, Chen, W, Pfeffer, S, Rajewsky, N, Meister, G. A human snoRNA with microRNA‐like functions. Mol Cell 2008, 32:519–528.
Cole, C, Sobala, A, Lu, C, Thatcher, SR, Bowman, A, Brown, JW, Green, PJ, Barton, GJ, Hutvagner, G. Filtering of deep sequencing data reveals the existence of abundant Dicer‐dependent small RNAs derived from tRNAs. RNA 2009, 15:2147–2160.
Lee, YS, Shibata, Y, Malhotra, A, Dutta, A. A novel class of small RNAs: tRNA‐derived RNA fragments (tRFs). Genes Dev 2009, 23:2639–2649.
Yang, JS, Maurin, T, Robine, N, Rasmussen, KD, Jeffrey, KL, Chandwani, R, Papapetrou, EP, Sadelain, M, O`Carroll, D, Lai, EC. Conserved vertebrate mir‐451 provides a platform for Dicer‐independent, Ago2‐mediated microRNA biogenesis. Proc Natl Acad Sci U S A 2010, 107:15163–15168.
Cifuentes, D, Xue, H, Taylor, DW, Patnode, H, Mishima, Y, Cheloufi, S, Ma, E, Mane, S, Hannon, GJ, Lawson, ND, et al. A novel miRNA processing pathway independent of Dicer requires Argonaute2 catalytic activity. Science 2010, 328:1694–1698.
Cheloufi, S, Dos Santos, CO, Chong, MM, Hannon, GJ. A dicer‐independent miRNA biogenesis pathway that requires Ago catalysis. Nature 2010, 465:584–589.
Hutvagner, G, Zamore, PD. RNAi: nature abhors a double‐strand. Curr Opin Genet Dev 2002, 12:225–232.
Umbach, JL, Cullen, BR. The role of RNAi and microRNAs in animal virus replication and antiviral immunity. Genes Dev 2009, 23:1151–1164.
Zamore, PD, Tuschl, T, Sharp, PA, Bartel, DP. RNAi: double‐stranded RNA directs the ATP‐dependent cleavage of mRNA at 21 to 23 nucleotide intervals. Cell 2000, 101:25–33.
Ratcliff, FG, MacFarlane, SA, Baulcombe, DC. Gene silencing without DNA. RNA‐mediated cross‐protection between viruses. Plant Cell 1999, 11:1207–1216.
Parameswaran, P, Sklan, E, Wilkins, C, Burgon, T, Samuel, MA, Lu, R, Ansel, KM, Heissmeyer, V, Einav, S, Jackson, W, et al. Six RNA viruses and forty‐one hosts: viral small RNAs and modulation of small RNA repertoires in vertebrate and invertebrate systems. PLoS Pathog 2010, 6:e1000764.
Kim, VN, Han, J, Siomi, MC. Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 2009, 10:126–139.
Cullen, BR. Viruses and microRNAs: RISCy interactions with serious consequences. Genes Dev 2011, 25:1881–1894.
Cullen, BR. MicroRNAs as mediators of viral evasion of the immune system. Nat Immunol 2013, 14:205–210.
Pfeffer, S, Zavolan, M, Grasser, FA, Chien, M, Russo, JJ, Ju, J, John, B, Enright, AJ, Marks, D, Sander, C, et al. Identification of virus‐encoded microRNAs. Science 2004, 304:734–736.
Pfeffer, S, Sewer, A, Lagos‐Quintana, M, Sheridan, R, Sander, C, Grasser, FA, van Dyk, LF, Ho, CK, Shuman, S, Chien, M, et al. Identification of microRNAs of the herpesvirus family. Nat Methods 2005, 2:269–276.
Lin, YT, Sullivan, CS. Expanding the role of Drosha to the regulation of viral gene expression. Proc Natl Acad Sci U S A 2011, 108:11229–11234.
Andersson, MG, Haasnoot, PC, Xu, N, Berenjian, S, Berkhout, B, Akusjarvi, G. Suppression of RNA interference by adenovirus virus‐associated RNA. J Virol 2005, 79:9556–9565.
Umbach, JL, Kramer, MF, Jurak, I, Karnowski, HW, Coen, DM, Cullen, BR. MicroRNAs expressed by herpes simplex virus 1 during latent infection regulate viral mRNAs. Nature 2008, 454:780–783.
Skalsky, RL, Cullen, BR. Viruses, microRNAs, and host interactions. Annu Rev Microbiol 2009, 64:123–141.
Shapiro, JS, Langlois, RA, Pham, AM, Tenoever, BR. Evidence for a cytoplasmic microprocessor of pri‐miRNAs. RNA 2012, 18:1338–1346.
Backes, S, Shapiro, JS, Sabin, LR, Pham, AM, Reyes, I, Moss, B, Cherry, S, Tenoever, BR. Degradation of host microRNAs by poxvirus poly(A) polymerase reveals terminal RNA methylation as a protective antiviral mechanism. Cell Host Microbe 2012, 12:200–210.
Rouha, H, Thurner, C, Mandl, CW. Functional microRNA generated from a cytoplasmic RNA virus. Nucleic Acids Res 2010, 38:8328–8337.
Varble, A, Chua, MA, Perez, JT, Manicassamy, B, Garcia‐Sastre, A, tenOever, BR. Engineered RNA viral synthesis of microRNAs. Proc Natl Acad Sci U S A 2010, 107:11519–11524.
Shapiro, JS, Varble, A, Pham, AM, Tenoever, BR. Noncanonical cytoplasmic processing of viral microRNAs. RNA 2010, 16:2068–2074.
Langlois, RA, Shapiro, JS, Pham, AM, tenOever, BR. In vivo delivery of cytoplasmic RNA virus‐derived miRNAs. Mol Ther 2012, 20:367–375.
Kincaid, RP, Burke, JM, Sullivan, CS. RNA virus microRNA that mimics a B‐cell oncomiR. Proc Natl Acad Sci U S A 2012, 109:3077–3082.
Kuhn, RJ, ed. Togaviridae: The Viruses and Their Replication. 5th ed. Philadelphia, PA: Lippincott Williams %26 Wilkins; 2007.
Zeng, Y, Cullen, BR. Efficient processing of primary microRNA hairpins by Drosha requires flanking nonstructured RNA sequences. J Biol Chem 2005, 280:27595–27603.
Bogerd, HP, Karnowski, HW, Cai, X, Shin, J, Pohlers, M, Cullen, BR. A mammalian herpesvirus uses noncanonical expression and processing mechanisms to generate viral MicroRNAs. Mol Cell 2010, 37:135–142.
Hussain, M, Torres, S, Schnettler, E, Funk, A, Grundhoff, A, Pijlman, GP, Khromykh, AA, Asgari, S. West Nile virus encodes a microRNA‐like small RNA in the 3′ untranslated region which up‐regulates GATA4 mRNA and facilitates virus replication in mosquito cells. Nucleic Acids Res 2011, 5:2210–2223.
Henke, JI, Goergen, D, Zheng, J, Song, Y, Schuttler, CG, Fehr, C, Junemann, C. Niepmann M: microRNA‐122 stimulates translation of hepatitis C virus RNA. EMBO J 2008, 27:3300–3310.
Orom, UA, Nielsen, FC, Lund, AH. MicroRNA‐10a binds the 5′UTR of ribosomal protein mRNAs and enhances their translation. Mol Cell 2008, 30:460–471.
Vasudevan, S, Tong, Y, Steitz, JA. Switching from repression to activation: microRNAs can up‐regulate translation. Science 2007, 318:1931–1934.
Perez, JT, Varble, A, Sachidanandam, R, Zlatev, I, Manoharan, M, Garcia‐Sastre, A, tenOever, BR. Influenza A virus‐generated small RNAs regulate the switch from transcription to replication. Proc Natl Acad Sci U S A 2010, 107:11525–11530.
Czech, B, Hannon, GJ. Small RNA sorting: matchmaking for Argonautes. Nat Rev Genet 2011, 12:19–31.
Tang, X, Zhang, Y, Tucker, L, Ramratnam, B. Phosphorylation of the RNase III enzyme Drosha at Serine300 or Serine302 is required for its nuclear localization. Nucleic Acids Res 2010, 38:6610–6619.
Han, J, Pedersen, JS, Kwon, SC, Belair, CD, Kim, YK, Yeom, KH, Yang, WY, Haussler, D, Blelloch, R, Kim, VN. Posttranscriptional crossregulation between Drosha and DGCR8. Cell 2009, 136:75–84.
Kadener, S, Rodriguez, J, Abruzzi, KC, Khodor, YL, Sugino, K, Marr, MT 2nd, Nelson, S, Rosbash, M. Genome‐wide identification of targets of the drosha‐pasha/DGCR8 complex. RNA 2009, 15:537–545.

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

Processing of virus‐derived cytoplasmic primary‐microRNAs

Related Articles

Browse by Topic

Access to this WIREs title is by subscription only.

The latest WIREs articles in your inbox