Skip to main content
SpringerLink
Log in

Function of GW182 and GW Bodies in siRNA and miRNA Pathways

  • Chapter
  • First Online:
Ten Years of Progress in GW/P Body Research

Part of the book series: Advances in Experimental Medicine and Biology ((volume 768))

Abstract

GW182 is an 182 kDa protein with multiple glycine/tryptophan repeats (GW or WG) playing a central role in siRNA- and miRNA-mediated gene silencing. GW182 interacts with its functional partner Argonaute proteins (AGO) via multiple domains to exert its silencing activity in both pathways. In siRNA-mediated silencing, knockdown either GW182 or Ago2 causes loss of silencing activity correlating with the disassembly of GWBs. In contrast, GW182 and its longer isoform TNGW1 appear to be downstream repressors that function independent of Ago2, whereas the Ago2-GW182 interaction is critical for the localization of Ago2 in the cytoplasmic foci and its repression function. GW182 contains two non-overlapping repression domains that can trigger translational repression with mild effect on mRNA decay. Collectively, GW182 plays a critical role in miRNA-mediated gene silencing.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Anderson P, Kedersha N (2006) RNA granules. J Cell Biol 172:803–808

    Article  PubMed  CAS  Google Scholar 

  • Anderson P, Kedersha N (2009) RNA granules: post-transcriptional and epigenetic modulators of gene expression. Nat Rev Mol Cell Biol 10:430–436

    Article  PubMed  CAS  Google Scholar 

  • Baillat D, Shiekhattar R (2009) Functional dissection of the human TNRC6 (GW182-related) family of proteins. Mol Cell Biol 29:4144–4155

    Article  PubMed  CAS  Google Scholar 

  • Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233

    Article  PubMed  CAS  Google Scholar 

  • Behm-Ansmant I, Rehwinkel J, Doerks T, Stark A, Bork P, Izaurralde E (2006) mRNA degradation by miRNAs and GW182 requires both CCR4:NOT deadenylase and DCP1:DCP2 decapping complexes. Genes Dev 20:1885–1898

    Article  PubMed  CAS  Google Scholar 

  • Braun JE, Huntzinger E, Fauser M, Izaurralde E (2011) GW182 proteins directly recruit ­cytoplasmic deadenylase complexes to miRNA targets. Mol Cell 44:120–133

    Article  PubMed  CAS  Google Scholar 

  • Chekulaeva M, Filipowicz W, Parker R (2009) Multiple independent domains of dGW182 ­function in miRNA-mediated repression in Drosophila. RNA 15:794–803

    Article  PubMed  CAS  Google Scholar 

  • Chekulaeva M, Parker R, Filipowicz W (2010) The GW/WG repeats of Drosophila GW182 function as effector motifs for miRNA-mediated repression. Nucleic Acids Res 38:6673–6683

    Article  PubMed  CAS  Google Scholar 

  • Chekulaeva M, Mathys H, Zipprich JT, Attig J, Colic M, Parker R, Filipowicz W (2011) miRNA repression involves GW182-mediated recruitment of CCR4-NOT through conserved W-containing motifs. Nat Struct Mol Biol 18:1218–1226

    Article  PubMed  CAS  Google Scholar 

  • Chen CY, Zheng D, Xia Z, Shyu AB (2009) Ago-TNRC6 triggers microRNA-mediated decay by promoting two deadenylation steps. Nat Struct Mol Biol 16:1160–1166

    Article  PubMed  CAS  Google Scholar 

  • Ding L, Spencer A, Morita K, Han M (2005) The developmental timing regulator AIN-1 interacts with miRISCs and may target the argonaute protein ALG-1 to cytoplasmic P bodies in C. ­elegans. Mol Cell 19:437–447

    Article  PubMed  CAS  Google Scholar 

  • Ebert MS, Neilson JR, Sharp PA (2007) MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat Methods 4:721–726

    Article  PubMed  CAS  Google Scholar 

  • El-Shami M, Pontier D, Lahmy S, Braun L, Picart C, Vega D, Hakimi MA, Jacobsen SE, Cooke R, Lagrange T (2007) Reiterated WG/GW motifs form functionally and evolutionarily conserved ARGONAUTE-binding platforms in RNAi-related components. Genes Dev 21:2539–2544

    Article  PubMed  CAS  Google Scholar 

  • Erickson SL, Lykke-Andersen J (2011) Cytoplasmic mRNP granules at a glance. J Cell Sci 124:293–297

    Article  PubMed  CAS  Google Scholar 

  • Eulalio A, Rehwinkel J, Stricker M, Huntzinger E, Yang SF, Doerks T, Dorner S, Bork P, Boutros M, Izaurralde E (2007) Target-specific requirements for enhancers of decapping in miRNA-mediated gene silencing. Genes Dev 21:2558–2570

    Article  PubMed  CAS  Google Scholar 

  • Eulalio A, Helms S, Fritzsch C, Fauser M, Izaurralde E (2009a) A C-terminal silencing domain in GW182 is essential for miRNA function. RNA 15:1067–1077

    Article  PubMed  CAS  Google Scholar 

  • Eulalio A, Tritschler F, Buttner R, Weichenrieder O, Izaurralde E, Truffault V (2009b) The RRM domain in GW182 proteins contributes to miRNA-mediated gene silencing. Nucleic Acids Res 37:2974–2983

    Article  PubMed  CAS  Google Scholar 

  • Eulalio A, Tritschler F, Izaurralde E (2009c) The GW182 protein family in animal cells: new insights into domains required for miRNA-mediated gene silencing. RNA 15:1433–1442

    Article  PubMed  CAS  Google Scholar 

  • Eystathioy T, Chan EK, Tenenbaum SA, Keene JD, Griffith K, Fritzler MJ (2002) A phosphorylated cytoplasmic autoantigen, GW182, associates with a unique population of human mRNAs within novel cytoplasmic speckles. Mol Biol Cell 13:1338–1351

    Article  PubMed  CAS  Google Scholar 

  • Eystathioy T, Jakymiw A, Chan EK, Seraphin B, Cougot N, Fritzler MJ (2003) The GW182 protein colocalizes with mRNA degradation associated proteins hDcp1 and hLSm4 in cytoplasmic GW bodies. RNA 9:1171–1173

    Article  PubMed  CAS  Google Scholar 

  • Fabian MR, Mathonnet G, Sundermeier T, Mathys H, Zipprich JT, Svitkin YV, Rivas F, Jinek M, Wohlschlegel J, Doudna JA, Chen CY, Shyu AB, Yates JR 3rd, Hannon GJ, Filipowicz W, Duchaine TF, Sonenberg N (2009) Mammalian miRNA RISC recruits CAF1 and PABP to affect PABP-dependent deadenylation. Mol Cell 35:868–880

    Article  PubMed  CAS  Google Scholar 

  • Fabian MR, Sonenberg N, Filipowicz W (2010) Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem 79:351–379

    Article  PubMed  CAS  Google Scholar 

  • Fabian MR, Cieplak MK, Frank F, Morita M, Green J, Srikumar T, Nagar B, Yamamoto T, Raught B, Duchaine TF, Sonenberg N (2011) miRNA-mediated deadenylation is orchestrated by GW182 through two conserved motifs that interact with CCR4-NOT. Nat Struct Mol Biol 18:1211–1217

    Article  PubMed  CAS  Google Scholar 

  • Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114

    Article  PubMed  CAS  Google Scholar 

  • Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391:806–811

    Article  PubMed  CAS  Google Scholar 

  • Huntzinger E, Izaurralde E (2011) Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet 12:99–110

    Article  PubMed  CAS  Google Scholar 

  • Hutvagner G, Simard MJ (2008) Argonaute proteins: key players in RNA silencing. Nat Rev Mol Cell Biol 9:22–32

    Article  PubMed  CAS  Google Scholar 

  • Jakymiw A, Lian S, Eystathioy T, Li S, Satoh M, Hamel JC, Fritzler MJ, Chan EK (2005) Disruption of GW bodies impairs mammalian RNA interference. Nat Cell Biol 7:1267–1274

    Article  PubMed  Google Scholar 

  • Jakymiw A, Pauley KM, Li S, Ikeda K, Lian S, Eystathioy T, Satoh M, Fritzler MJ, Chan EK (2007) The role of GW/P-bodies in RNA processing and silencing. J Cell Sci 120:1317–1323

    Article  PubMed  CAS  Google Scholar 

  • Jinek M, Doudna JA (2009) A three-dimensional view of the molecular machinery of RNA interference. Nature 457:405–412

    Article  PubMed  CAS  Google Scholar 

  • Jinek M, Fabian MR, Coyle SM, Sonenberg N, Doudna JA (2010) Structural insights into the human GW182-PABC interaction in microRNA-mediated deadenylation. Nat Struct Mol Biol 17:238–240

    Article  PubMed  CAS  Google Scholar 

  • Kahvejian A, Svitkin YV, Sukarieh R, M’Boutchou MN, Sonenberg N (2005) Mammalian poly(A)-binding protein is a eukaryotic translation initiation factor, which acts via multiple mechanisms. Genes Dev 19:104–113

    Article  PubMed  CAS  Google Scholar 

  • Krol J, Loedige I, Filipowicz W (2010) The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 11:597–610

    PubMed  CAS  Google Scholar 

  • Lazzaretti D, Tournier I, Izaurralde E (2009) The C-terminal domains of human TNRC6A, TNRC6B, and TNRC6C silence bound transcripts independently of Argonaute proteins. RNA 15:1059–1066

    Article  PubMed  CAS  Google Scholar 

  • Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854

    Article  PubMed  CAS  Google Scholar 

  • Li S, Lian SL, Moser JJ, Fritzler ML, Fritzler MJ, Satoh M, Chan EK (2008) Identification of GW182 and its novel isoform TNGW1 as translational repressors in Ago2-mediated silencing. J Cell Sci 121:4134–4144

    Article  PubMed  CAS  Google Scholar 

  • Lian S, Jakymiw A, Eystathioy T, Hamel JC, Fritzler MJ, Chan EKL (2006) GW bodies, microRNAs and the cell cycle. Cell Cycle 5:242–245

    Article  PubMed  CAS  Google Scholar 

  • Lian S, Fritzler MJ, Katz J, Hamazaki T, Terada N, Satoh M, Chan EK (2007) Small interfering RNA-mediated silencing induces target-dependent assembly of GW/P bodies. Mol Biol Cell 18:3375–3387

    Article  PubMed  CAS  Google Scholar 

  • Lian SL, Li S, Abadal GX, Pauley BA, Fritzler MJ, Chan EKL (2009) The C-terminal half of human Ago2 binds to multiple GW-rich regions of GW182 and requires GW182 to mediate silencing. RNA 15:804–813

    Article  PubMed  CAS  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  PubMed  CAS  Google Scholar 

  • Liu J, Rivas FV, Wohlschlegel J, Yates JR 3rd, Parker R, Hannon GJ (2005) A role for the P-body component GW182 in microRNA function. Nat Cell Biol 7:1261–1266

    PubMed  Google Scholar 

  • Meaux S, van Hoof A, Baker KE (2008) Nonsense-mediated mRNA decay in yeast does not require PAB1 or a poly(A) tail. Mol Cell 29:134–140

    Article  PubMed  CAS  Google Scholar 

  • Miyoshi K, Okada TN, Siomi H, Siomi MC (2009) Characterization of the miRNA-RISC loading complex and miRNA-RISC formed in the Drosophila miRNA pathway. RNA 15:1282–1291

    Article  PubMed  CAS  Google Scholar 

  • Pasquinelli AE, Reinhart BJ, Slack F, Martindale MQ, Kuroda MI, Maller B, Hayward DC, Ball EE, Degnan B, Muller P, Spring J, Srinivasan A, Fishman M, Finnerty J, Corbo J, Levine M, Leahy P, Davidson E, Ruvkun G (2000) Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 408:86–89

    Article  PubMed  CAS  Google Scholar 

  • Pauley KM, Eystathioy T, Jakymiw A, Hamel JC, Fritzler MJ, Chan EK (2006) Formation of GW bodies is a consequence of microRNA genesis. EMBO Rep 7:904–910

    Article  PubMed  CAS  Google Scholar 

  • Pauley KM, Satoh M, Pauley BA, Dominguez-Gutierrez PR, Wallet SM, Holliday LS, Cha S, Reeves WH, Chan EKL (2010) Formation of GW/P bodies as marker for microRNA-mediated regulation of innate immune signaling in THP-1 cells. Immunol Cell Biol 88:205–212

    Article  PubMed  CAS  Google Scholar 

  • Pillai RS, Artus CG, Filipowicz W (2004) Tethering of human Ago proteins to mRNA mimics the miRNA-mediated repression of protein synthesis. RNA 10:1518–1525

    Article  PubMed  CAS  Google Scholar 

  • Rana TM (2007) Illuminating the silence: understanding the structure and function of small RNAs. Nat Rev Mol Cell Biol 8:23–36

    Article  PubMed  CAS  Google Scholar 

  • Schneider MD, Najand N, Chaker S, Pare JM, Haskins J, Hughes SC, Hobman TC, Locke J, Simmonds AJ (2006) Gawky is a component of cytoplasmic mRNA processing bodies required for early Drosophila development. J Cell Biol 174:349–358

    Article  PubMed  CAS  Google Scholar 

  • Sheth U, Parker R (2003) Decapping and decay of messenger RNA occur in cytoplasmic ­processing bodies. Science 300:805–808

    Article  PubMed  CAS  Google Scholar 

  • Takimoto K, Wakiyama M, Yokoyama S (2009) Mammalian GW182 contains multiple ­Argonaute-binding sites and functions in microRNA-mediated translational repression. RNA 15:1078–1089

    Article  PubMed  CAS  Google Scholar 

  • Teixeira D, Sheth U, Valencia-Sanchez MA, Brengues M, Parker R (2005) Processing bodies require RNA for assembly and contain nontranslating mRNAs. RNA 11:371–382

    Article  PubMed  CAS  Google Scholar 

  • Till S, Lejeune E, Thermann R, Bortfeld M, Hothorn M, Enderle D, Heinrich C, Hentze MW, Ladurner AG (2007) A conserved motif in Argonaute-interacting proteins mediates functional interactions through the Argonaute PIWI domain. Nat Struct Mol Biol 14:897–903

    Article  PubMed  CAS  Google Scholar 

  • Tritschler F, Huntzinger E, Izaurralde E (2010) Role of GW182 proteins and PABPC1 in the miRNA pathway: a sense of deja vu. Nat Rev Mol Cell Biol 11:379–384

    PubMed  CAS  Google Scholar 

  • Yang Z, Jakymiw A, Wood MR, Eystathioy T, Rubin RL, Fritzler MJ, Chan EK (2004) GW182 is critical for the stability of GW bodies expressed during the cell cycle and cell proliferation. J Cell Sci 117:5567–5578

    Article  PubMed  CAS  Google Scholar 

  • Yao B, Li S, Jung HM, Lian SL, Abadal GX, Han F, Fritzler MJ, Chan EKL (2011) Divergent GW182 functional domains in the regulation of translational silencing. Nucleic Acids Res 39:2534–2547

    Article  PubMed  CAS  Google Scholar 

  • Zekri L, Huntzinger E, Heimstadt S, Izaurralde E (2009) 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 29:6220–6231

    Article  PubMed  CAS  Google Scholar 

  • Zipprich JT, Bhattacharyya S, Mathys H, Filipowicz W (2009) Importance of the C-terminal domain of the human GW182 protein TNRC6C for translational repression. RNA 15:781–793

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA

    Bing Yao

  2. Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA

    Songqing Li

  3. Department of Oral Biology, Health Science Center, University of Florida, 100424, Gainesville, FL, 32610, USA

    Edward K. L. Chan

Authors
  1. Bing Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Songqing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Edward K. L. Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Edward K. L. Chan .

Editor information

Editors and Affiliations

  1. College of Dentistry, Department of Oral Biology, University of Florida, Southwest Archer Road 1600, Gainesville, 32610, Florida, USA

    Edward K. L. Chan

  2. Dept. Medicine & Medical Biochemistry, University of Calgary, Hospital Drive NW., 3330, Calgary, T2N 4N1, Alberta, Canada

    Marvin J. Fritzler

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Yao, B., Li, S., Chan, E.K.L. (2013). Function of GW182 and GW Bodies in siRNA and miRNA Pathways. In: Chan, E., Fritzler, M. (eds) Ten Years of Progress in GW/P Body Research. Advances in Experimental Medicine and Biology, vol 768. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5107-5_6

Download citation

Publish with us

Policies and ethics

Search

Navigation