Abstract
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.
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References
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.
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.
Baker K. E. and Parker R. (2004) Nonsense-mediated mRNA decay: terminating erroneous gene expression. Curr. Opin. Cell Biol. 16, 293–299.
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.
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.
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.
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.
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.
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.
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.
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.
Dostie J. and Dreyfuss G. (2002) Translation is required to remove Y14 from mRNAs in the cytoplasm. Curr. Biol. 12, 1060–1067.
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.
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.
Fan X. C. and Steitz J. A. (1998) HNS, a nuclear-cytoplasmic shuttling sequence in HuR. Proc. Natl. Acad. Sci. USA. 95, 15293–15298.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Keene J. D. (2003) Organizing mRNA export. Nat. Genet. 33, 111–112.
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.
Knowles R. B., Sabry J. H., Martone M. E., et al. (1996) Translocation of RNA granules in living neurons. J. Neurosci. 16, 7812–7820.
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.
Krichevsky A. M. and Kosik K. S. (2001) Neuronal RNA granules: a link between RNA localization and stimulation-dependent translation. Neuron 32, 683–696.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Maniatis T. and Reed R. (2002) An extensive network of coupling among gene expression machines. Nature 416, 499–506.
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.
Martin K. C. and Kosik K. S. (2002) Synaptic tagging—who’s it? Nat. Rev. Neurosci. 3, 813–820.
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.
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.
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.
Monshausen M., Putz U., Rehbein M., et al. (2001) Two rat brain staufen isoforms differentially bind RNA. J. Neurochem. 76, 155–165.
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.
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.
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.
Reed R. (2003) Coupling transcription, splicing and mRNA export. Curr. Opin. Cell Biol. 15, 326–331.
Reed R. and Hurt E. (2002) A conserved mRNA export machinery coupled to pre-mRNA splicing. Cell 108, 523–531.
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.
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.
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.
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.
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.
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.
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.
Strasser K., Masuda S., Mason P., et al. (2002) TREX is a conserved complex coupling transcription with messenger RNA export. Nature 417, 304–308.
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.
Stutz F. and Izaurralde E. (2003) The interplay of nuclear mRNP assembly, mRNA surveillance and export. Trends Cell Biol. 13, 319–327.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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Monshausen, M., Gehring, N.H. & Kosik, K.S. The mammalian RNA-binding protein staufen2 links nuclear and cytoplasmic RNA processing pathways in neurons. Neuromol Med 6, 127–144 (2004). https://doi.org/10.1385/NMM:6:2-3:127
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DOI: https://doi.org/10.1385/NMM:6:2-3:127