Skip to main content

Thank you for visiting 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.

Messenger RNA targeting to endoplasmic reticulum stress signalling sites


Deficiencies in the protein-folding capacity of the endoplasmic reticulum (ER) in all eukaryotic cells lead to ER stress and trigger the unfolded protein response (UPR)1,2,3. ER stress is sensed by Ire1, a transmembrane kinase/endoribonuclease, which initiates the non-conventional splicing of the messenger RNA encoding a key transcription activator, Hac1 in yeast or XBP1 in metazoans. In the absence of ER stress, ribosomes are stalled on unspliced HAC1 mRNA. The translational control is imposed by a base-pairing interaction between the HAC1 intron and the HAC1 5′ untranslated region4. After excision of the intron, transfer RNA ligase joins the severed exons5,6, lifting the translational block and allowing synthesis of Hac1 from the spliced HAC1 mRNA to ensue4. Hac1 in turn drives the UPR gene expression program comprising 7–8% of the yeast genome7 to counteract ER stress. Here we show that, on activation, Ire1 molecules cluster in the ER membrane into discrete foci of higher-order oligomers, to which unspliced HAC1 mRNA is recruited by means of a conserved bipartite targeting element contained in the 3′ untranslated region. Disruption of either Ire1 clustering or HAC1 mRNA recruitment impairs UPR signalling. The HAC1 3′ untranslated region element is sufficient to target other mRNAs to Ire1 foci, as long as their translation is repressed. Translational repression afforded by the intron fulfils this requirement for HAC1 mRNA. Recruitment of mRNA to signalling centres provides a new paradigm for the control of eukaryotic gene expression.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: A conserved element in the 3′ UTR of HAC1 mRNA is required for splicing in vivo , but not in vitro.
Figure 3: The HAC1 mRNA/Ire1 foci are functional UPR signalling centres.
Figure 2: In response to ER stress HAC1 mRNA localizes to Ire1 foci in a 3′ BE-dependent manner.
Figure 4: Translational repression is a prerequisite for mRNA targeting to Ire1 foci.


  1. 1

    Bernales, S., Papa, F. R. & Walter, P. Intracellular signaling by the unfolded protein response. Annu. Rev. Cell Dev. Biol. 22, 487–508 (2006)

    CAS  Article  Google Scholar 

  2. 2

    Ron, D. & Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response. Nature Rev. Mol. Cell Biol. 8, 519–529 (2007)

    CAS  Article  Google Scholar 

  3. 3

    van Anken, E. & Braakman, I. Endoplasmic reticulum stress and the making of a professional secretory cell. Crit. Rev. Biochem. Mol. Biol. 40, 269–283 (2005)

    Article  Google Scholar 

  4. 4

    Rüegsegger, U., Leber, J. H. & Walter, P. Block of HAC1 mRNA translation by long-range base pairing is released by cytoplasmic splicing upon induction of the unfolded protein response. Cell 107, 103–114 (2001)

    Article  Google Scholar 

  5. 5

    Sidrauski, C., Cox, J. S. & Walter, P. tRNA ligase is required for regulated mRNA splicing in the unfolded protein response. Cell 87, 405–413 (1996)

    CAS  Article  Google Scholar 

  6. 6

    Sidrauski, C. & Walter, P. The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response. Cell 90, 1031–1039 (1997)

    CAS  Article  Google Scholar 

  7. 7

    Travers, K. J. et al. Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell 101, 249–258 (2000)

    CAS  Article  Google Scholar 

  8. 8

    Gonzalez, T. N., Sidrauski, C., Dörfler, S. & Walter, P. Mechanism of nonspliceosomal mRNA splicing in the unfolded protein response pathway. EMBO J. 18, 3119–3132 (1999)

    CAS  Article  Google Scholar 

  9. 9

    Brodsky, A. S. & Silver, P. A. Pre-mRNA processing factors are required for nuclear export. RNA 6, 1737–1749 (2000)

    CAS  Article  Google Scholar 

  10. 10

    Diehn, M., Eisen, M. B., Botstein, D. & Brown, P. O. Large-scale identification of secreted and membrane-associated gene products using DNA microarrays. Nature Genet. 25, 58–62 (2000)

    CAS  Article  Google Scholar 

  11. 11

    Kimata, Y. et al. Two regulatory steps of ER-stress sensor Ire1 involving its cluster formation and interaction with unfolded proteins. J. Cell Biol. 179, 75–86 (2007)

    CAS  Article  Google Scholar 

  12. 12

    Brengues, M., Teixeira, D. & Parker, R. Movement of eukaryotic mRNAs between polysomes and cytoplasmic processing bodies. Science 310, 486–489 (2005)

    ADS  CAS  Article  Google Scholar 

  13. 13

    Teixeira, D. & Parker, R. Analysis of P-body assembly in Saccharomyces cerevisiae . Mol. Biol. Cell 18, 2274–2287 (2007)

    CAS  Article  Google Scholar 

  14. 14

    Ghaemmaghami, S. et al. Global analysis of protein expression in yeast. Nature 425, 737–741 (2003)

    ADS  CAS  Article  Google Scholar 

  15. 15

    Credle, J. J., Finer-Moore, J. S., Papa, F. R., Stroud, R. M. & Walter, P. On the mechanism of sensing unfolded protein in the endoplasmic reticulum. Proc. Natl Acad. Sci. USA 102, 18773–18784 (2005)

    ADS  CAS  Article  Google Scholar 

  16. 16

    Pollock, R. & Rivera, V. M. Regulation of gene expression with synthetic dimerizers. Methods Enzymol. 306, 263–281 (1999)

    CAS  Article  Google Scholar 

  17. 17

    Chartrand, P., Meng, X. H., Huttelmaier, S., Donato, D. & Singer, R. H. Asymmetric sorting of Ash1p in yeast results from inhibition of translation by localization elements in the mRNA. Mol. Cell 10, 1319–1330 (2002)

    CAS  Article  Google Scholar 

  18. 18

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

    CAS  Article  Google Scholar 

  19. 19

    Parker, R. & Sheth, U. P bodies and the control of mRNA translation and degradation. Mol. Cell 25, 635–646 (2007)

    CAS  Article  Google Scholar 

  20. 20

    Kindler, S., Wang, H., Richter, D. & Tiedge, H. RNA transport and local control of translation. Annu. Rev. Cell Dev. Biol. 21, 223–245 (2005)

    CAS  Article  Google Scholar 

  21. 21

    Choi, S. B. et al. Messenger RNA targeting of rice seed storage proteins to specific ER subdomains. Nature 407, 765–767 (2000)

    ADS  CAS  Article  Google Scholar 

  22. 22

    Takizawa, P. A., DeRisi, J. L., Wilhelm, J. E. & Vale, R. D. Plasma membrane compartmentalization in yeast by messenger RNA transport and a septin diffusion barrier. Science 290, 341–344 (2000)

    ADS  CAS  Article  Google Scholar 

  23. 23

    Czaplinski, K. & Singer, R. H. Pathways for mRNA localization in the cytoplasm. Trends Biochem. Sci. 31, 687–693 (2006)

    CAS  Article  Google Scholar 

  24. 24

    Harding, H. P., Zhang, Y. & Ron, D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397, 271–274 (1999)

    ADS  CAS  Article  Google Scholar 

  25. 25

    Shamu, C. E. & Walter, P. Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus. EMBO J. 15, 3028–3039 (1996)

    CAS  Article  Google Scholar 

  26. 26

    Bromley, S. K. et al. The immunological synapse. Annu. Rev. Immunol. 19, 375–396 (2001)

    CAS  Article  Google Scholar 

  27. 27

    Maddock, J. R. & Shapiro, L. Polar location of the chemoreceptor complex in the Escherichia coli cell. Science 259, 1717–1723 (1993)

    ADS  CAS  Article  Google Scholar 

  28. 28

    Korennykh, A. V. et al. The unfolded protein response signals through high-order assembly of Ire1. Nature 10.1038/nature07661 (this issue)

  29. 29

    Lee, K. P. et al. Structure of the dual enzyme Ire1 reveals the basis for catalysis and regulation in nonconventional RNA splicing. Cell 132, 89–100 (2008)

    CAS  Article  Google Scholar 

  30. 30

    Guthrie, C. & Fink, G. R. Guide to Yeast Genetics and Molecular and Cell Biology (Academic, 2002)

    Google Scholar 

  31. 31

    Longtine, M. S. et al. Additional modules for versatile and economical PCR-based gene deletion and modification in Saccharomyces cerevisiae . Yeast 14, 953–961 (1998)

    CAS  Article  Google Scholar 

  32. 32

    Sambrook, J., Maniatis, T. & Fritsch, E. F. Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Laboratory, 1989)

    Google Scholar 

  33. 33

    Sikorski, R. S. & Hieter, P. A system of shuttle vectors and yeast host strains designed for efficient manipulation of DNA in Saccharomyces cerevisiae . Genetics 122, 19–27 (1989)

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Sheff, M. A. & Thorn, K. S. Optimized cassettes for fluorescent protein tagging in Saccharomyces cerevisiae . Yeast 21, 661–670 (2004)

    CAS  Article  Google Scholar 

Download references


We thank M. Jonikas and B. Kornmann for their help with the MatLab scripts; R. Parker for the pPS2037 and pRP1187 plasmids; K. Thorn for the pKT127 plasmid and for his assistance with microscopy at the Nikon Imaging Center at UCSF; and C. Guthrie, R. Andino, J. Gross and members of the Walter laboratory for discussion and comments on the manuscript. T.A. was supported by the Basque Foundation for Science and the Howard Hughes Medical Institute; E.v.A. by the Netherlands Organization for Scientific Research (NWO); D.P. and C.A.R. by the National Science Foundation; C.A.R. by the President’s Dissertation Year Fellowship; and A.V.K. by the Jane Childs Memorial Fund for Medical Research. P.W. is an Investigator of the Howard Hughes Medical Institute.

Author Contributions T.A. and E.v.A. wrote the manuscript, conceived the experiments and together with D.P. carried out most of the experimental work. I.M.S. and E.v.A. observed Ire1 foci, and C.A.R. performed all experiments concerning tRNA ligase localization. A.V.K. carried out kinetic analyses. P.W. directed the research programme and writing of the manuscript.

Author information



Corresponding author

Correspondence to Tomás Aragón.

Supplementary information

Supplementary Information 1

This file contains Supplementary Figures S1-S4 with Legends. (PDF 8494 kb)

Supplementary Information 2

This file contains the script which calculates (1) The fraction of Ire1 concentrated in foci and (2) The colocalization index (CI), that scores for the fraction of RNA foci colocalizing with Ire1. (TXT 2 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Aragón, T., van Anken, E., Pincus, D. et al. Messenger RNA targeting to endoplasmic reticulum stress signalling sites. Nature 457, 736–740 (2009).

Download citation

Further reading


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.


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