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:

Formation of stress granules inhibits apoptosis by suppressing stress-responsive MAPK pathways

Nature Cell Biology volume 10, pages 1324–1332 (2008)Cite this article

This article has been updated

Abstract

When confronted with environmental stress, cells either activate defence mechanisms to survive, or initiate apoptosis, depending on the type of stress. Certain types of stress, such as hypoxia, heatshock and arsenite (type 1 stress), induce cells to assemble cytoplasmic stress granules (SGs), a major adaptive defence mechanism. SGs are multimolecular aggregates of stalled translation pre-initiation complexes that prevent the accumulation of mis-folded proteins1. Type 2 stress, which includes X-rays and genotoxic drugs, induce apoptosis through the stress-activated p38 and JNK MAPK (SAPK) pathways. A functional relationship between the SG and SAPK responses is unknown. Here, we report that SG formation negatively regulates the SAPK apoptotic response, and that the signalling scaffold protein RACK1 functions as a mediator between the two responses. RACK1 binds to the stress-responsive MTK1 MAPKKK and facilitates its activation by type 2 stress; however, under conditions of type 1 stress, RACK1 is sequestered into SGs. Thus, type 1 conditions suppress activation of the MTK1–SAPK pathway and apoptosis induced by type 2 stress. These findings may be relevant to the problem of hypoxia-induced resistance to cancer chemotherapy.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: RACK1 binds MTK1.
Figure 2: RACK1 enhances MTK1 activation.
Figure 3: Recruitment of RACK1 into cytoplasmic SGs.
Figure 4: SG formation suppresses SAPK-mediated apoptosis.
Figure 5: RACK1 mediates crosstalk between SG formation and SAPK pathways.

Similar content being viewed by others

Change history

  • 18 November 2008

    In the version of this article initially published online, the last paragraph before Methods, incorrectly read "...type 2 stress suppresses the apoptosis induced by type 1 stress, by..." This sentence should read "...type 1 stress suppresses the apoptosis induced by type 2 stress, by...". This error has been corrected in the HTML and PDF versions of the article.

References

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Tourriere, H. et al. The RasGAP-associated endoribonuclease G3BP asembles stress granules. J. Cell Biol. 160, 823–831 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kedersha, N. et al. Evidence that ternary complex (eIF2–GTP-tRNAiMet)-defective preinitiation complexs are core constituents of mammalian stress granules. Mol. Biol. Cell 13, 195–210 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kim, W. J., Back, S. H., Kim, V., Ryu, I. & Jang, S. K. Sequestration of TRAF2 into stress granules interrupts tumor necrosis factor signaling under stress conditions. Mol. Cell. Biol. 25, 2450–2462 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Deigendesch, N., Koch-Nolte, F. & Rothenburg, S. ZBP1 subcellular localization and association with stress granules is controlled by its Z-DNA binding domain. Nucleic Acids Res. 34, 5007–5020 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chen, Z. et al. MAP kinases. Chem. Rev. 101, 2449–2476 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Takekawa, M., Posas, F. & Saito, H. A human homolog of the yeast Ssk2/Ssk22 MAP kinase kinase kinases, MTK1, mediates stress-induced activation of the p38 and JNK pathways. EMBO J. 16, 4973–4982 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gerwins, P., Blank, J. L. & Johnson, G. L. Cloning of a novel mitogen-activated protein kinase kinase kinase, MEKK4, that selectively regulates the c-Jun amino terminal kinase pathway. J. Biol. Chem. 272, 8288–8295 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Ichijo, H. et al. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 275, 90–94 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Yamaguchi, K. et al. Identification of a member of the MAPKKK family as a potential mediator of TGF-β signal transduction. Science 270, 2008–2011 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Takekawa, M. & Saito, H. A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Cell 95, 521–530 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Mita, H., Tsutsui, J., Takekawa, M., Witten, E. A. & Saito, H. Regulation of MTK1/MEKK4 kinase activity by its N-terminal autoinhibitory domain and GADD45 binding. Mol. Cell. Biol. 22, 4544–4555 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Miyake, Z., Takekawa, M., Ge, Q. & Saito, H. Activation of MTK1/MEKK4 by GADD45 through induced N–C dissociation and dimerization-mediated trans autophosphorylation of the MTK1 kinase domain. Mol. Cell. Biol. 27, 2765–2776 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fornace, A. J. Jr., Alamo, I. Jr. & Hollander, M. C. DNA damage-inducible transcripts in mammalian cells. Proc. Natl Acad. Sci. USA 85, 8800–8804 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lievermann, D. A. & Hoffman, B. Gadd45 in the response of hematopoietic cells to genotoxic stress. Blood Cells Mol. Dis. 39, 329–335 (2007).

    Article  Google Scholar 

  16. Takekawa, M., Tatebayashi, K. & Saito, H. Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases. Mol. Cell 18, 295–306 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Ron, D. et al. Cloning of an intracellular receptor for protein kinase C: a homolog of the beta subunit of G proteins. Proc. Natl Acad. Sci. USA 91, 839–843 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nilsson, J., Sengupta, J., Frank, J. & Nissen, P. Regulation of eukaryotic translation by the RACK1 protein: a platform for signalling molecules on the ribosome. EMBO Rep. 5, 1137–1141 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lopez-Bergami, P. et al. RACK1 mediates activation of JNK by protein kinase C. Mol. Cell 19, 309–320 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Shibuya, H. et al. TAB1: an activator of the TAK1 MAPKKK in TGF-beta signal transduction. Science 272, 1179–1182 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Kimball, S. R., Horetsky, R. L., Ron, D., Jefferson, L. S. & Harding, H. P. Mammalian stress granules represent sites of accumulation of stalled translation initiation complexes. Am. J. Physiol. Cell Physiol. 284, 273–284 (2002).

    Article  Google Scholar 

  22. Kedersha, N. L., Gupta, M., Li, W., Miller, I. & Anderson, P. RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2α to the assembly of mammalian stress granules. J. Cell Biol. 147, 1431–1441 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tian, Q., Streuli, M., Saito, H., Schlossman, S. F. & Anderson, P. A polyadenylate binding protein localized to the granules of cytolytic lmphocytes induces DNA fragmentation in target cells. Cell 67, 629–639 (1991).

    Article  CAS  PubMed  Google Scholar 

  24. Sengupta, J. et al. Identification of the versatile scaffold protein RACK 1 on the eukaryotic ribosome by cryo-EM. Nature Struct. Mol. Biol. 11, 957–962 (2004).

    Article  CAS  Google Scholar 

  25. Kayali, F., Montie, H. L., Rafols, J. A. & DeGracia, D. J. Prolonged translation arrest in reperfused hippocampal cornu Ammonis 1 is mediated by stress granules. Neuroscience 134, 1223–1245 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Moeller, B. J., Cao, Y., Li, C. Y. & Dewhirst, M. W. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 5, 429–441 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Harris, A. L. Hypoxia - a key regulatory factor in tumour growth. Nature Rev. Cancer 2, 38–47 (2002).

    Article  CAS  Google Scholar 

  28. Brown, J. M. & Wilson, W. R. Exploiting tumour hypoxia in cancer treatment. Nature Rev. Cancer 4, 437–447 (2004).

    Article  CAS  Google Scholar 

  29. Takekawa, M., Maeda, T. & Saito, H. Protein phosphatase 2Cα inhibits the human stress-responsive p38 and JNK MAPK pathways. EMBO J. 17, 4744–4752 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chi, H., Lu, B., Takekawa, M., Davis, R. J. & Flavell, R. A. GADD45β/GADD45γ and MEKK4 comprise a genetic pathway mediating STAT4-independent IFNγ production in T cells. EMBO J. 23, 1576–1586 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported in part by several grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (M.T. and H.S.), and by a PRESTO programme from the Japan Science and Technology Agency (M.T.). We thank P. O'Grady for critical reading of the manuscript and T. Chano (Shiga University of Medical Science), S. Iwata (University of Tokyo), K. Matsumoto (Nagoya University) and H. Ichijo (University of Tokyo) for plasmids.

Author information

Authors and Affiliations

  1. Department of Molecular Cell Signaling, Institute of Medical Sciences, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, 108-8639, Tokyo, Japan

    Kyoko Arimoto, Haruo Saito & Mutsuhiro Takekawa

  2. Medical Proteomics Laboratory, Institute of Medical Sciences, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, 108-8639, Tokyo, Japan

    Hiroyuki Fukuda & Shinobu Imajoh-Ohmi

  3. Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-0033, Tokyo, Japan

    Kyoko Arimoto, Haruo Saito & Mutsuhiro Takekawa

Authors
  1. Kyoko Arimoto
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Hiroyuki Fukuda
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Shinobu Imajoh-Ohmi
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Haruo Saito
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Mutsuhiro Takekawa
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

K.A. and M.T. designed and performed the experiments; H.F. and S.I.-O. performed the mass spectrometry analyses; K.A., M.T. and H.S. analysed the data and wrote the paper.

Corresponding authors

Correspondence to Haruo Saito or Mutsuhiro Takekawa.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 1920 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Arimoto, K., Fukuda, H., Imajoh-Ohmi, S. et al. Formation of stress granules inhibits apoptosis by suppressing stress-responsive MAPK pathways. Nat Cell Biol 10, 1324–1332 (2008). https://doi.org/10.1038/ncb1791

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1791

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