NeuroMolecular Medicine

, Volume 6, Issue 2–3, pp 127–144 | Cite as

The mammalian RNA-binding protein staufen2 links nuclear and cytoplasmic RNA processing pathways in neurons

  • Michaela Monshausen
  • Niels H. Gehring
  • Kenneth S. Kosik
Original Article


Members of the Staufen family of RNA-binding proteins are highly conserved cytoplasmic RNA transporters associated with RNA granules. staufen2 is specifically expressed in neurons where the delivery of RNA to dendrites is thought to have a role in plasticity. We found that Staufen2 interacts with the nuclear pore protein p62, with the RNA export protein Tap and with the exon-exon junction complex (EJC) proteins Y14-Mago. The interaction of Staufen2 with the Y14-Mago heterodimer seems to represent a highly conserved complex as the same proteins are involved in the Staufen-mediated localization of oskar mRNA in Drosophila oocytes. A pool of Staufen2 is present in neuronal nuclei and colocalizes to a large degree with p62 and partly with Tap, Y14, and Mago. We suggest a model whereby a set of conserved genes in the oskar mRNA export pathway may be recruited to direct a dendritic destination for mRNAs originating as a Staufen2 nuclear complex.

Index Entries

Staufen nuclear pore protein p62 Tap Y14 Mago RNA transport RNA export RNA processing NMD EJC 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Antic D. and Keene J. D. (1998) Messenger ribonucleoprotein complexes containing human ELAV proteins: interactions with cytoskeleton and translational apparatus. J. Cell Sci. 111, 183–197.PubMedGoogle Scholar
  2. Bachi A., Braun I. C., Rodrigues J. P., et al. (2000) The C-terminal domain of TAP interacts with the nuclear pore complex and promotes export of specific CTE-bearing RNA substrates. RNA. 6, 136–158.PubMedCrossRefGoogle Scholar
  3. Baker K. E. and Parker R. (2004) Nonsense-mediated mRNA decay: terminating erroneous gene expression. Curr. Opin. Cell Biol. 16, 293–299.PubMedCrossRefGoogle Scholar
  4. Bear J., Tan W., Zolotukhin A. S., Tabernero C., Hudson E. A. and Felber B. K. (1999) Identification of novel import and export signals of human TAP, the protein that binds to the constitutive transport element of the type D retrovirus mRNAs. Mol. Cell Biol. 19, 6306–6317.PubMedGoogle Scholar
  5. Blevins M. B., Smith A. M., Phillips E. M., and Powers M. A. (2003) Complex formation among the RNA export proteins Nup98, Rael/Gle2, and TAP. J. Biol. Chem. 278, 20979–20988.PubMedCrossRefGoogle Scholar
  6. Braun I. C., Herold A., Rode M., Conti E., and Izaurralde E. (2001) Overexpression of TAP/p15 heterodimers bypasses nuclear retention and stimulates nuclear mRNA export. J. Biol. Chem. 276, 20536–20543.PubMedCrossRefGoogle Scholar
  7. Braun I. C., Rohrbach E., Schmitt C. and Izaurralde E. (1999) TAP binds to the constitutive transport element (CTE) through a novel RNA-binding motif that is sufficient to promote CTE-dependent RNA export from the nucleus. Embo. J. 18, 1953–1965.PubMedCrossRefGoogle Scholar
  8. Chan C. C., Dostie J., Diem M. D., et al. (2004) eIF4A3 is a novel component of the exon junction complex. RNA. 10, 200–209.PubMedCrossRefGoogle Scholar
  9. Dargemont C., Schmidt-Zachmann M. S., and Kuhn L. C. (1995) Direct interaction of nucleoporin p62 with mRNA during its export from the nucleus. J. Cell Sci. 108, 257–263.PubMedGoogle Scholar
  10. Darnell J. C., Jensen K. B., Jin P., Brown V., Warren S. T., and Darnell R. B. (2001) Fragile X mental retardation protein targets G quartet mRNAs important for neuronal function. Cell 107, 489–499.PubMedCrossRefGoogle Scholar
  11. Degot S., Le Hir H., Alpy F., et al. (2004) Association of the breast cancer protein MLN51 with the exon junction complex via its SpEckle localizer and RNA binding (SELOR) module. J. Biol. Chem. 279, 33702–33715.PubMedCrossRefGoogle Scholar
  12. Dostie J. and Dreyfuss G. (2002) Translation is required to remove Y14 from mRNAs in the cytoplasm. Curr. Biol. 12, 1060–1067.PubMedCrossRefGoogle Scholar
  13. Dreyfuss G., Kim V. N., and Kataoka N. (2002) Messenger-RNA-binding proteins and the messages they carry. Nat. Rev. Mol. Cell Biol. 3, 195–205.PubMedCrossRefGoogle Scholar
  14. Duchaine T. F., Hemraj I., Furic L., Deitinghoff A., Kiebler M. A., and DesGroseillers L. (2002) Staufen2 isoforms localize to the somatodendritic domain of neurons and interact with different organelles. J. Cell Sci. 115, 3285–3295.PubMedGoogle Scholar
  15. Fan X. C. and Steitz J. A. (1998) HNS, a nuclear-cytoplasmic shuttling sequence in HuR. Proc. Natl. Acad. Sci. USA. 95, 15293–15298.PubMedCrossRefGoogle Scholar
  16. Ferraiuolo M. A., Lee C. S., Ler L. W., et al. (2004) A nuclear translation-like factor eIF4AIII is recruited to the mRNA during splicing and functions in non-sense-mediated decay. Proc. Natl. Acad. Sci. USA. 101, 4118–4123.PubMedCrossRefGoogle Scholar
  17. Fribourg S., Gatfield D., Izaurralde E., and Conti E. (2003) A novel mode of RBD-protein recognition in the Y14-Mago complex. Nat. Struct. Biol. 10, 433–439.PubMedCrossRefGoogle Scholar
  18. Gehring N. H., Neu-Yilik G., Schell T., Hentze M. W., and Kulozik A. E. (2003) Y14 and hUpf3b form an NMD-activating complex. Mol. Cell. 11, 939–949.PubMedCrossRefGoogle Scholar
  19. Gruter P., Tabernero C., von Kobbe C., et al. (1998) TAP, the human homolog of Mex67p, mediates CTE-dependent RNA export from the nucleus. Mol. Cell 1, 649–659.PubMedCrossRefGoogle Scholar
  20. Guan T., Muller S., Klier G., et al. (1995) Structural analysis of the p62 complex, an assembly of O-linked glycoproteins that localizes near the central gated channel of the nuclear pore complex. Mol. Biol. Cell 6, 1591–1603.PubMedGoogle Scholar
  21. Hachet O. and Ephrussi A. (2001) Drosophila Y14 shuttles to the posterior of the oocyte and is required for oskar mRNA transport. Curr. Biol. 11, 1666–1674.PubMedCrossRefGoogle Scholar
  22. Ho D.N., Coburn G. A., Kang Y., Cullen B. R. and Georgiadis M. M. (2002) The crystal structure and mutational analysis of a novel RNA-binding domain found in the human Tap nuclear mRNA export factor. Proc. Natl. Acad. Sci. USA. 99, 1888–1893.PubMedCrossRefGoogle Scholar
  23. Hu T., Guan T., and Gerace L. (1996) Molecular and functional characterization of the p62 complex, an assembly of nuclear pore complex glycoproteins. J. Cell Biol. 134, 589–601.PubMedCrossRefGoogle Scholar
  24. Huang Y., Gattoni R., Stevenin J., and Steitz J. A. (2003) SR splicing factors serve as adapter proteins for TAP-dependent mRNA export. Mol. Cell 11, 837–843.PubMedCrossRefGoogle Scholar
  25. Jin L., Guzik B. W., Bor Y. C., Rekosh D., and Hammarskjold M. L. (2003) Tap and NXT promote translation of unspliced mRNA. Genes Dev. 17, 3075–3086.PubMedCrossRefGoogle Scholar
  26. Kang Y. and Cullen B. R. (1999) The human Tap protein is a nuclear mRNA export factor that contains novel RNA-binding and nucleocytoplasmic transport sequences. Genes Dev. 13, 1126–1139.PubMedGoogle Scholar
  27. Katahira J., Straesser K., Saiwaki T., Yoneda Y., and Hurt E. (2002) Complex formation between Tap and p15 affects binding to FG-repeat nucleoporins and nucleocytoplasmic shuttling. J. Biol. Chem. 277, 9242–9246.PubMedCrossRefGoogle Scholar
  28. Katahira J., Strasser K., Podtelejnikov A., Mann M., Jung J. U., and Hurt E. (1999) The Mex67p-mediated nuclear mRNA export pathway is conserved from yeast to human. Embo. J. 18, 2593–2609.PubMedCrossRefGoogle Scholar
  29. Kataoka N., Diem M. D., Kim V. N., Yong J., and Dreyfuss G. (2001) Magoh, a human homolog of Drosophila mago nashi protein, is a component of the splicing-dependent exon-exon junction complex. Embo. J. 20, 6424–6433.PubMedCrossRefGoogle Scholar
  30. Kataoka N., Yong J., Kim V. N., et al. (2000) Pre-mRNA splicing imprints mRNA in the nucleus with a novel RNA-binding protein that persists in the cytoplasm. Mol. Cell 6, 673–682.PubMedCrossRefGoogle Scholar
  31. Keene J. D. (2003) Organizing mRNA export. Nat. Genet. 33, 111–112.PubMedCrossRefGoogle Scholar
  32. Kiebler M. A., Hemraj I., Verkade P., et al. (1999) The mammalian staufen protein localizes to the somatodendritic domain of cultured hippocampal neurons: implications for its involvement in mRNA transport. J. Neurosci. 19, 288–297.PubMedGoogle Scholar
  33. Knowles R. B., Sabry J. H., Martone M. E., et al. (1996) Translocation of RNA granules in living neurons. J. Neurosci. 16, 7812–7820.PubMedGoogle Scholar
  34. Kohrmann M., Luo M., Kaether C., DesGroseillers L., Dotti C. G., and Kiebler M. A. (1999) Microtubule-dependent recruitment of Staufen-green fluorescent protein into large RNA-containing granules and subsequent dendritic transport in living hippocampal neurons. Mol. Biol. Cell 10, 2945–2953.PubMedGoogle Scholar
  35. Krichevsky A. M. and Kosik K. S. (2001) Neuronal RNA granules: a link between RNA localization and stimulation-dependent translation. Neuron 32, 683–696.PubMedCrossRefGoogle Scholar
  36. Lau C. K., Diem M. D., Dreyfuss G., and Van Duyne G. D. (2003) Structure of the Y14-Magoh core of the exon junction complex. Curr. Biol. 13, 933–941.PubMedCrossRefGoogle Scholar
  37. Le Hir H., Gatfield D., Izaurralde E. and Moore M. J. (2001) The exon-exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay. Embo. J. 20, 4987–4997.PubMedCrossRefGoogle Scholar
  38. Le Hir H., Izaurralde E., Maquat L. E., and Moore M. J. (2000) The spliceosome deposits multiple proteins 20–24 nucleotides upstream of mRNA exon-exon junctions. Embo. J. 19, 6860–6869.PubMedCrossRefGoogle Scholar
  39. Le S., Sternglanz R., and Greider C. W. (2000) Identification of two RNA-binding proteins associated with human telomerase RNA. Mol. Biol. Cell 11, 999–1010.PubMedGoogle Scholar
  40. Lejeune F., Ishigaki Y., Li X., and Maquat L. E. (2002) The exon junction complex is detected on CBP80-bound but not eIF4E-bound mRNA in mammalian cells: dynamics of mRNP remodeling. Embo. J. 21, 3536–3545.PubMedCrossRefGoogle Scholar
  41. Levesque L., Guzik B., Guan T., et al. (2001) RNA export mediated by tap involves NXT1-dependent interactions with the nuclear pore complex. J. Biol. Chem. 276, 44953–44962.PubMedCrossRefGoogle Scholar
  42. Luo M. L., Zhou Z., Magni K., et al. (2001) Pre-mRNA splicing and mRNA export linked by direct interactions between UAP56 and Aly. Nature 413, 644–647.PubMedCrossRefGoogle Scholar
  43. Macchi P., Brownawell A. M., Grunewald B., DesGroseillers L., Macara I. G., and Kiebler M. A. (2004) The brain specific double-stranded RNA-binding protein Staufen2: nucleolar accumulation and isoform specific exportin-5 dependent export. J. Biol. Chem. Google Scholar
  44. Macchi P., Kroening S., Palacios I. M., et al. (2003) Barentsz, a new component of the Staufen-containing ribonucleoprotein particles in mammalian cells, interacts with Staufen in an RNA-dependent manner. J. Neurosci. 23, 5778–5788.PubMedGoogle Scholar
  45. Mallardo M., Deitinghoff A., Muller J., et al. (2003) Isolation and characterization of Staufen-containing ribonucleoprotein particles from rat brain. Proc. Natl. Acad. Sci. USA. 100, 2100–2105.PubMedCrossRefGoogle Scholar
  46. Maniatis T. and Reed R. (2002) An extensive network of coupling among gene expression machines. Nature 416, 499–506.PubMedCrossRefGoogle Scholar
  47. Marion R. M., Fortes P., Beloso A., Dotti C., and Ortin J. (1999) A human sequence homologue of Staufen is an RNA-binding protein that is associated with polysomes and localizes to the rough endoplasmic reticulum. Mol. Cell Biol. 19, 2212–2219.PubMedGoogle Scholar
  48. Martin K. C. and Kosik K. S. (2002) Synaptic tagging—who’s it? Nat. Rev. Neurosci. 3, 813–820.PubMedCrossRefGoogle Scholar
  49. Micklem D. R., Adams J., Grunert S., and St Johnston D. (2000) Distinct roles of two conserved Staufen domains in oskar mRNA localization and translation. Embo. J. 19, 1366–1377.PubMedCrossRefGoogle Scholar
  50. Micklem D. R., Dasgupta R., Elliott H., et al. (1997) The mago nashi gene is required for the polarisation of the oocyte and the formation of perpendicular axes in Drosophila. Curr. Biol. 7, 468–478.PubMedCrossRefGoogle Scholar
  51. Miller S., Yasuda M., Coats J. K., Jones Y., Martone M. E. and Mayford M. (2002) Disruption of dendritic translation of CaMKIIalpha impairs stabilization of synaptic plasticity and memory consolidation. Neuron 36, 507–519.PubMedCrossRefGoogle Scholar
  52. Monshausen M., Putz U., Rehbein M., et al. (2001) Two rat brain staufen isoforms differentially bind RNA. J. Neurochem. 76, 155–165.PubMedCrossRefGoogle Scholar
  53. Monshausen M. R. M., Richter D. and Kindler S. (2002) The RNA-binding protein Staufen from rat brain interacts with protein phosphatase 1. J. Neurochem. 81, 557–564.PubMedCrossRefGoogle Scholar
  54. Nielsen J., Adolph S. K., Rajpert-De Meyts E., et al. (2003) Nuclear transit of human zipcode-binding protein IMP1. Biochem. J. 376, 383–391.PubMedCrossRefGoogle Scholar
  55. Palacios I. M., Gatfield D., St Johnston D., and Izaurralde E. (2004) An eIF4AIII-containing complex required for mRNA localization and nonsense-mediated mRNA decay. Nature 427, 753–757.PubMedCrossRefGoogle Scholar
  56. Reed R. (2003) Coupling transcription, splicing and mRNA export. Curr. Opin. Cell Biol. 15, 326–331.PubMedCrossRefGoogle Scholar
  57. Reed R. and Hurt E. (2002) A conserved mRNA export machinery coupled to pre-mRNA splicing. Cell 108, 523–531.PubMedCrossRefGoogle Scholar
  58. Rook M. S., Lu M., and Kosik K. S. (2000) CaMKIIalpha 3′ untranslated region-directed mRNA translocation in living neurons: visualization by GFP linkage. J. Neurosci. 20, 6385–6393.PubMedGoogle Scholar
  59. Schell T., Kulozik A. E., and Hentze M. W. (2002) Integration of splicing, transport and translation to achieve mRNA quality control by the nonsense-mediated decay pathway. Genome Biol. 3.Google Scholar
  60. Schmitt I. and Gerace L. (2001) In vitro analysis of nuclear transport mediated by the C-terminal shuttle domain of Tap. J. Biol. Chem. 276, 42355–42363.PubMedCrossRefGoogle Scholar
  61. Shan J., Munro T. P., Barbarese E., Carson J. H., and Smith R. (2003) A molecular mechanism for mRNA trafficking in neuronal dendrites. J. Neurosci. 23, 8859–8866.PubMedGoogle Scholar
  62. Shibuya T., Tange T. O., Sonenberg N., and Moore M. J. (2004) eIF4AIII binds spliced mRNA in the exon junction complex and is essential for nonsense-mediated decay. Nat Struct. Mol. Biol. 11, 346–351.PubMedCrossRefGoogle Scholar
  63. Steward O., Wallace C. S., Lyford G. L., and Worley P. F. (1998) Synaptic activation causes the mRNA for the IEG Arc to localize selectively near activated postsynaptic sites on dendrites. Neuron 21, 741–751.PubMedCrossRefGoogle Scholar
  64. Strasser K. and Hurt E. (2000) Yra1p, a conserved nuclear RNA-binding protein, interacts directly with Mex67p and is required for mRNA export. Embo. J. 19, 410–420.PubMedCrossRefGoogle Scholar
  65. Strasser K., Masuda S., Mason P., et al. (2002) TREX is a conserved complex coupling transcription with messenger RNA export. Nature 417, 304–308.PubMedCrossRefGoogle Scholar
  66. Stutz F., Bachi A., Doerks T., et al. (2000) REF, an evolutionary conserved family of hnRNP-like proteins, interacts with TAP/Mex67p and participates in mRNA nuclear export. RNA 6, 638–650.PubMedCrossRefGoogle Scholar
  67. Stutz F. and Izaurralde E. (2003) The interplay of nuclear mRNP assembly, mRNA surveillance and export. Trends Cell Biol. 13, 319–327.PubMedCrossRefGoogle Scholar
  68. Tang S. J., Meulemans D., Vazquez L., Colaco N., and Schuman E. (2001) A role for a rat homolog of staufen in the transport of RNA to neuronal dendrites. Neuron 32, 463–475.PubMedCrossRefGoogle Scholar
  69. Tange T. O., Nott A. and Moore M. J. (2004) The ever-increasing complexities of the exon junction complex. Curr. Opin. Cell Biol. 16, 279–284.PubMedCrossRefGoogle Scholar
  70. van Eeden F. J., Palacios I. M., Petronczki M., Weston M. J., and St Johnston D. (2001) Barentsz is essential for the posterior localization of oskar mRNA and colocalizes with it to the posterior pole. J. Cell Biol. 154, 511–523.PubMedCrossRefGoogle Scholar
  71. Wickham L., Duchane T., Luo M., Nabi I. R., and DesGroseillers L. (1999) Mammalian staufen is a double-stranded-RNA- and tubulin-binding protein which localizes to the rough endoplasmic reticulum. Mol. Cell Biol. 19, 2220–2230.PubMedGoogle Scholar
  72. Wiegand H. L., Coburn G. A., Zeng Y., Kang Y., Bogerd H. P., and Cullen B. R. (2002) Formation of Tap/NXT1 heterodimers activates Tap-dependent nuclear mRNA export by enhancing recruitment to nuclear pore complexes. Mol. Cell Biol. 22, 245–256.PubMedCrossRefGoogle Scholar
  73. Xie C. X., Ozawa H., Yang Y. M., and Kawata M. (2000) Immunohistochemical study of nucleoporin p62 in the hippocampus and hypothalamus of the rat brain. Neuroreport 11, 2965–2967.PubMedCrossRefGoogle Scholar
  74. Zalfa F., Giorgi M., Primerano B., et al. (2003) The fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses. Cell 112, 317–327.PubMedCrossRefGoogle Scholar
  75. Zhou Z., Luo M. J., Straesser K., Katahira J., Hurt E., and Reed R. (2000) The protein Aly links pre-messenger-RNA splicing to nuclear export in metazoans. Nature 407 (6802), 401–405.PubMedCrossRefGoogle Scholar
  76. Zolotukhin A. S., Tan W., Bear J., Smulevitch S., and Felber B. K. (2002) U2AF participates in the binding of TAP (NXF1) to mRNA. J. Biol. Chem. 277, 3935–3942.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2004

Authors and Affiliations

  • Michaela Monshausen
    • 1
  • Niels H. Gehring
    • 2
  • Kenneth S. Kosik
    • 3
  1. 1.Department of NeurologyBrigham and Women’s Hospital, and Harvard Medical SchoolBoston
  2. 2.Molecular Medicine Partnership UnitUniversity of Heidelberg & European Molecular Biology LaboratoryHeidelbergGermany
  3. 3.Neuroscience Research InstituteUniversity of CaliforniaSanta Barbara

Personalised recommendations