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

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

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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.

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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.

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  • 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.

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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.

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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

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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.

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Correspondence to Haruo Saito or Mutsuhiro Takekawa.

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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

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