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Depletion of PDCD4 Accelerates Stress Granule Assembly Through Sensitization of Stress Response Pathways

  • Kim, Jeeho (Department of Cellular & Molecular Medicine, College of Medicine, Chosun University) ;
  • Chang, In Youb (Department of Anatomy, College of Medicine, Chosun University) ;
  • Lee, Wooje (Department of Cellular & Molecular Medicine, College of Medicine, Chosun University) ;
  • Ohn, Takbum (Department of Cellular & Molecular Medicine, College of Medicine, Chosun University)
  • Received : 2019.11.28
  • Accepted : 2019.12.16
  • Published : 2019.12.30

Abstract

Programmed cell death 4 (PDCD4) is a novel tumor suppressor that function in the nucleus and the cytoplasm and appears to be involved in the regulation of transcription and translation. Stress granules (SGs) are cytoplasmic foci at which untranslated mRNAs accumulate when cells exposed to environmental stresses. Since PDCD4 has implicated in translation repression through direct interaction with eukaryotic translation initiation factor 4A (eIF4A), we here investigated if PDCD4 has a functional role in the process of SG assembly under oxidative stresses. Using immunofluorescence microscopy, we found that PDCD4 is localized to SGs under oxidative stresses. Next, we tested if knockdown of PDCD4 has an effect on the assembly of SG using PDCD4-specific siRNA. Interestingly, SG assembly was accelerated and this effect was caused by sensitization of phosphorylation of eIF2α and dephosphorylation of eIF4E binding protein (4E-BP). These results suggest that PDCD4 has an effect on SG dynamics and possibly involved in cap-dependent translation repression under stress conditions.

Keywords

References

  1. Q. Wang, and H. S. Yang, "The role of Pdcd4 in tumour suppression and protein translation", Biol. Cell, doi:10.1111/boc.201800014, 2018.
  2. J. H. Leupold, H. S. Yang, N. H. Colburn, I. Asangani, S. Post, and H. Allgayer, "Tumor suppressor Pdcd4 inhibits invasion/intravasation and regulates urokinase receptor (u-PAR) gene expression via Sp-transcription factors", Oncogene, Vol. 26, pp. 4550-4562, 2007. https://doi.org/10.1038/sj.onc.1210234
  3. Q. Wang, Z. Sun, and H. S. Yang, "Downregulation of tumor suppressor Pdcd4 promotes invasion and activates both ${\beta}$-catenin/Tcf and AP-1-dependent transcription in colon carcinoma cells", Oncogene, Vol. 27, pp.1527-1535, 2008. https://doi.org/10.1038/sj.onc.1210793
  4. S. Matsuhashi, M. Manirujjaman, H. Hamajima, and I. Ozaki, "Control mechnisms of the Tumor Suppressor PDCD4: Expression and Functions", Int. J. Mol. Sci., Vol. 20, p. E2304, 2019.
  5. J. H. Chang, Y. H. Cho, S. Y. Sohn, J. M. Choi, A. Kim, Y. C. Kim, S. K. Jang, and Y. Cho, "Crys tal structure of the eIF4A-PDCD4 complex", Proc Natl Acad Sci USA., Vol. 106, pp. 3148-3153, 2009. https://doi.org/10.1073/pnas.0808275106
  6. M. D. Panas, P. Ivanov, and P. Anderson, "Mechanistic insights into mammalian stress granule dynamics", J. Cell Biol., Vol. 215, pp. 313-323, 2016. https://doi.org/10.1083/jcb.201609081
  7. P. Anderson, and N. Kedersha, "Stress granules: the Tao of RNA triage", Trends Biochem. Sci., Vol. 33, pp. 141-150, 2008. https://doi.org/10.1016/j.tibs.2007.12.003
  8. N. Kedersha, P. Ivanov, and P. Anderson, "Stress granules and cell signaling: more than just a passing phase?", Trends Biochem. Sci., Vol. 38, pp. 494-506, 2013. https://doi.org/10.1016/j.tibs.2013.07.004
  9. J. R. Buchan, and R. Parker, "Eukaryotic stress granules: the ins and outs of translation", Mol. Cell, Vol. 36, pp. 932-941, 2009. https://doi.org/10.1016/j.molcel.2009.11.020
  10. S. Boeynaems, S. Alberti, N. L. Fawzi, T. Mittag, M. Polymenidou, F. Rousseau, J. Schymkowitz, J. Shorter, B. Wolozin, L. V. D. Bosch, P. Tompa, and M. Fuxreiter, "Protein phase separation: A New Phase in Cell Biology", Trends Cell Biol., Vol. 28, pp. 420-435, 2018. https://doi.org/10.1016/j.tcb.2018.02.004
  11. T. Ohn, N. Kedersha, T. Hickman, S. Tisdale, and P. Anderson, "A functional RNAi screen links OGlcNAc modification of ribosomal proteins to stress granule and processing body assembly", Nat. Cell Biol., Vol. 10, pp. 1224-1231, 2008. https://doi.org/10.1038/ncb1783
  12. A. K. Jayabalan, A. Sanchez, R. Y. Park, S. P. Yoon, G. Y. Kang, J. H. Baek, P. Anderson, Y. Kee, and T. Ohn, "NEDDylation promotes stress granule assembly", Nat. Commun., Vol. 7, pp. 12125, 2016. https://doi.org/10.1038/ncomms12125
  13. M. M. Emara, K. Fujimura, D. Sciaranghella, V. Ivanova, P. Ivanov, and P. Anderson, "Hydrogen peroxide induces stress granule formation independent of eIF2${\alpha}$ phosphorylation", Biochem. Biophys. Res. Commun., Vol. 423, pp. 763-769, 2012. https://doi.org/10.1016/j.bbrc.2012.06.033