Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

The protein Aly links pre-messenger-RNA splicing to nuclear export in metazoans

Nature volume 407, pages 401–405 (2000)Cite this article

Abstract

In metazoans, most pre-messenger RNAs contain introns that are removed by splicing. The spliced mRNAs are then exported to the cytoplasm. Recent studies showed that splicing promotes efficient mRNA export1, but the mechanism for coupling these two processes is not known. Here we show that Aly, the metazoan homologue of the yeast mRNA export factor Yra1p (ref. 2), is recruited to messenger ribonucleoprotein (mRNP) complexes generated by splicing. In contrast, Aly does not associate with mRNPs assembled on identical mRNAs that already have no introns or with heterogenous nuclear RNP (hnRNP) complexes. Aly is recruited during spliceosome assembly, and then becomes tightly associated with the spliced mRNP. Aly shuttles between the nucleus and cytoplasm, and excess recombinant Aly increases both the rate and efficiency of mRNA export in vivo. Consistent with its splicing-dependent recruitment, Aly co-localizes with splicing factors in the nucleus. We conclude that splicing is required for efficient mRNA export as a result of coupling between the splicing and the mRNA export machineries.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Purification of spliced messenger ribonucleoprotein (mRNP) that is functional in messenger RNA export.
Figure 2: Splicing-dependent recruitment of Aly to the spliced mRNPs.
Figure 3: Timing, specificity and stability of Aly recruitment.
Figure 4: Aly promotes mRNA export.
Figure 5: Aly co-localizes with splicing factors in nuclear speckles and shuttles between the nucleus and cytoplasm.

Similar content being viewed by others

References

  1. Luo, M. & Reed, R. Splicing is required for rapid and efficient mRNA export in metazoans. Proc. Natl Acad. Sci. USA 96, 14937–14942 (1999).

    Article  ADS  CAS  Google Scholar 

  2. Strasser, K. & Hurt, E. Yra1p, a conserved nuclear RNA-binding protein, interacts directly with Mex67p and is required for mRNA export. EMBO J. 19, 410–420 ( 2000).

    Article  CAS  Google Scholar 

  3. Le Hir, H., Moore, M. J. & Maquat, L. E. Pre-mRNA splicing alters mRNP composition: evidence for stable association of proteins at exon-exon junctions. Genes Dev. 14, 1098–1108 ( 2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Das, R., Zhou, Z. & Reed, R. Functional association of U2 snRNP with the ATP-independent spliceosomal complex E. Mol. Cell 5, 779–787 (2000).

    Article  CAS  Google Scholar 

  5. Hamm, J. & Mattaj, I. W. Monomethylated cap structures facilitate RNA export from the nucleus. Cell 63, 109–118 (1990).

    Article  CAS  Google Scholar 

  6. Stutz, F. et al. REF, an evolutionary conserved family of hnRNP-like proteins, interacts with TAP/Mex67p and participates in mRNA nuclear export. RNA 6, 638–650 ( 2000).

    Article  CAS  Google Scholar 

  7. Segref, A. et al. Mex67p, a novel factor for nuclear mRNA export, binds to both poly(A)+ RNA and nuclear pores. EMBO J. 16, 3256–3271 (1997).

    Article  CAS  Google Scholar 

  8. Gruter, P. et al. TAP, the human homolog of Mex67p, mediates CTE-dependent RNA export from the nucleus. Mol. Cell. 1, 649 –659 (1998).

    Article  CAS  Google Scholar 

  9. Ernst, R. K., Bray, M., Rekosh, D. & Hammarskjolk, M. L. A structured retroviral RNA element that mediates nucleocytoplasmic export of intron-containing RNA. Mol. Cell Biol. 17, 135– 144 (1997).

    Article  CAS  Google Scholar 

  10. Pasquinelli, A. E. et al. The constitutive transport element (CTE) of Mason–Pfizer monkey virus (MPMV) accesses a cellular mRNA export pathway. EMBO J. 16, 7500–7510 ( 1997).

    Article  CAS  Google Scholar 

  11. Saavedra, C., Felber, B. & Izaurralde, E. The simian retrovirus-1 constitutive transport element, unlike the HIV-1 RRE, uses factors required for cellular mRNA export. Curr. Biol. 7, 619–628 ( 1997).

    Article  CAS  Google Scholar 

  12. Bruhn, L., Munnerlyn, A. & Grosschedl, R. ALY, a context-dependent coactivator of LEF-1 and AML-1, is required for TCRalpha enhancer function. Genes Dev. 11, 640–653 (1997).

    Article  CAS  Google Scholar 

  13. Wichmann, I., Garcia-Lozano, J. R., Respaldiza, N., Gonzalez-Escribano, M. F. & Nunez-Roldan, A. Autoantibodies to transcriptional regulation proteins DEK and ALY in a patient with systemic lupus erythematosus. Hum. Immunol. 60, 57 –62 (1999).

    Article  CAS  Google Scholar 

  14. Portman, D. S., O'Connor, J. P. & Dreyfuss, G. YRA1, an essential Saccharomyces cerevisiae gene, encodes a novel nuclear protein with RNA annealing activity. RNA 3, 527–537 ( 1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Fu, X. D. The superfamily of arginine/serine-rich splicing factors. RNA 1, 663–680 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Bennett, M., Pinol-Roma, S., Staknis, D., Dreyfuss, G. & Reed, R. Differential binding of heterogeneous nuclear ribonucleoproteins to mRNA precursors prior to spliceosome assembly in vitro. Mol. Cell. Biol. 12, 3165– 3175 (1992).

    Article  CAS  Google Scholar 

  17. Dreyfuss, G., Matunis, M. J., Pinol-Roma, S. & Burd, C. G. hnRNP proteins and the biogenesis of mRNA. Annu. Rev. Biochem. 62, 289–321 ( 1993).

    Article  CAS  Google Scholar 

  18. Habets, W. J., Hoet, M. H., De Jong, B. A., Van der Kemp, A. & Van Venrooij, W. J. Mapping of B cell epitopes on small nuclear ribonucleoproteins that react with human autoantibodies as well as with experimentally-induced mouse monoclonal antibodies. J. Immunol. 143, 2560–2566 (1989).

    CAS  PubMed  Google Scholar 

  19. Achsel, T., Ahrens, K., Brahms, H., Teigelkamp, S. & Luhrmann, R. The human U5-220kD protein (hPrp8) forms a stable RNA-free complex with several U5-specific proteins, including an RNA unwindase, a homologue of ribosomal elongation factor EF-2, and a novel WD-40 protein. Mol. Cell. Biol. 18, 6756–6766 (1998).

    Article  CAS  Google Scholar 

  20. Fabrizio, P., Laggerbauer, B., Lauber, J., Lane, W. S. & Luhrmann, R. An evolutionarily conserved U5 snRNP-specific protein is a GTP-binding factor closely related to the ribosomal translocase EF-2. EMBO J. 16, 4092– 4106 (1997).

    Article  CAS  Google Scholar 

  21. Staley, J. P. & Guthrie, C. Mechanical devices of the spliceosome: motors, clocks, springs, and things. Cell 92, 315–326 (1998).

    Article  CAS  Google Scholar 

  22. Kang, Y. & Cullen, B. R. The human Tap protein is a nuclear mRNA export factor that contains novel RNA-binding and nucleocytoplasmic transport sequences. Genes Dev. 13, 1126– 1139 (1999).

    Article  CAS  Google Scholar 

  23. Katahira, J. et al. The Mex67p-mediated nuclear mRNA export pathway is conserved from yeast to human. EMBO J. 18, 2593– 2609 (1999).

    Article  CAS  Google Scholar 

  24. Spector, D. L. Macromolecular domains within the cell nucleus. Annu. Rev. Cell Biol. 9, 265–315 ( 1993).

    Article  CAS  Google Scholar 

  25. Fu, X. D. & Maniatis, T. Factor required for mammalian spliceosome assembly is localized to discrete regions in the nucleus. Nature 343, 437–441 ( 1990).

    Article  ADS  CAS  Google Scholar 

  26. Lewis, J. D. & Tollervey, D. Like attracts like: getting RNA processing together in the nucleus. Science 288, 1385–1389 (2000).

    Article  ADS  CAS  Google Scholar 

  27. Nakielny, S. & Dreyfuss, G. Transport of proteins and RNAs in and out of the nucleus. Cell 99, 677– 690 (1999).

    Article  CAS  Google Scholar 

  28. Pinol-Roma, S., Choi, Y. D., Matunis, M. J. & Dreyfuss, G. Immunopurification of heterogeneous nuclear ribonucleoprotein particles reveals an assortment of RNA-binding proteins. Genes Dev. 2 , 215–227 (1988); erratum Genes Dev. 2, 490 ( 1988).

    Article  CAS  Google Scholar 

  29. Pinol-Roma, S. & Dreyfuss, G. Shuttling of pre-mRNA binding proteins between nucleus and cytoplasm. Nature 355, 730–732 ( 1992).

    Article  ADS  CAS  Google Scholar 

  30. Reed, R. Protein composition of mammalian spliceosomes assembled in vitro. Proc. Natl Acad. Sci. USA 87, 8031– 8035 (1990).

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We are indebted to K. N. Clouse for discussions and comments on the manuscript. We thank R. Luhrmann for U5 antibodies, G. Dreyfuss for the hnRNP A1 and C antibodies, and A. Nunez-Roldan for the Aly antibody.

Author information

Author notes

  1. Zhaolan Zhou, Ming-juan Luo, Katja Straesser, Jun Katahira and Ed Hurt: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cell Biology, Harvard Medical School, Boston, 02115 , Massachusetts, USA

    Zhaolan Zhou, Ming-juan Luo & Robin Reed

  2. University of Heidelberg, Biochemie-Zentrum Heidelberg (BZH), Im Neuenheimer Feld 328, Heidelberg, D-69120 , Germany

    Katja Straesser, Jun Katahira & Ed Hurt

Authors
  1. Zhaolan Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ming-juan Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katja Straesser
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jun Katahira
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ed Hurt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Robin Reed
    View author publications

    You can also search for this author in PubMed Google Scholar

Supplementary Information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhou, Z., Luo, Mj., Straesser, K. et al. The protein Aly links pre-messenger-RNA splicing to nuclear export in metazoans. Nature 407, 401–405 (2000). https://doi.org/10.1038/35030160

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35030160

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing