Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
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Tunicamycin-Induced ER Stress Upregulates the Expression of Mitochondrial HtrA2 and Promotes Apoptosis Through the Cytosolic Release of HtrA2

  • Han, Chul (School of Life Sciences and Biotechnology, Korea University) ;
  • Nam, Min-Kyung (Research Institute of Molecular Genetics, College of Medicine, Catholic University of Korea) ;
  • Park, Hyo-Jin (School of Life Sciences and Biotechnology, Korea University) ;
  • Seong, Young-Mo (School of Life Sciences and Biotechnology, Korea University) ;
  • Kang, Seong-Man (School of Life Sciences and Biotechnology, Korea University) ;
  • Rhim, Hyang-Shuk (Research Institute of Molecular Genetics, College of Medicine, Catholic University of Korea)
  • Published : 2008.06.30
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Abstract

Recent studies provide some evidence that the HtrA2 protein is intimately associated with the pathogenesis of neurodegenerative disorders and that endoplasmic reticulum (ER) quality control and ER stress-associated cell death play critical roles in neuronal cell death. However, little is known about the intimate relationship between HtrA2 and ER stress-associated cellular responses. In the present study, we have demonstrated that the HtrA2 protein level was gradually and significantly increased by up to to-fold in the mitochondria under tunicamycin (Tm)-induced ER stress, which eventually promoted cell death through the release of HtrA2 into the cytoplasm. Using an ecdysone-inducible mammalian expression system, we demonstrate that the extent of cell death in 293-HtrA2 cells was approximately 20 times higher under Tm-induced ER stress, indicating that the increase in the HtrA2 protein level in the mitochondria itself is necessary but not sufficient for the promotion of cell death. Taken together, these results suggest that HtrA2 may serve as a mediator of ER stress-induced apoptosis and ER-mitochondrial cross-talk in some cellular processes.

Keywords

References

  1. Bertolotti, A., Y. Zhang, L. M. Hendershot, H. P. Harding, and D. Ron. 2000. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat. Cell Biol. 2: 326-332 https://doi.org/10.1038/35014014
  2. Boya, P., I. Cohen, N. Zamzami, H. L. Vieira, and G. Kroemer. 2002. Endoplasmic reticulum stress-induced cell death requires mitochondrial membrane permeabilization. Cell Death Differ. 9: 465-467 https://doi.org/10.1038/sj.cdd.4401006
  3. Danial, N. N. and S. J. Korsmeyer. 2004. Cell death: Critical control points. Cell 116: 205-219 https://doi.org/10.1016/S0092-8674(04)00046-7
  4. de Bruin, E. C., D. Meersma, J. de Wilde, I. den Otter, E. M. Schipper, J. P. Medema, and L. T. Peltenburg. 2003. A serine protease is involved in the initiation of DNA damage-induced apoptosis. Cell Death Differ. 10: 1204-1212 https://doi.org/10.1038/sj.cdd.4401296
  5. Egger, L., J. Schneider, C. Rheme, M. Tapernoux, J. Hacki, and C. Borner. 2003. Serine proteases mediate apoptosis-like cell death and phagocytosis under caspase-inhibiting conditions. Cell Death Differ. 10: 1188-1203 https://doi.org/10.1038/sj.cdd.4401288
  6. Faccio, L., C. Fusco, A. Chen, S. Martinotti, J. V. Bonventre, and A. S. Zervos. 2000. Characterization of a novel human serine protease that has extensive homology to bacterial heat shock endoprotease HtrA and is regulated by kidney ischemia. J. Biol. Chem. 275: 2581-2588 https://doi.org/10.1074/jbc.275.4.2581
  7. Garrido, C., L. Galluzzi, M. Brunet, P. E. Puig, C. Didelot, and G. Kroemer. 2006. Mechanisms of cytochrome c release from mitochondria. Cell Death Differ. 13: 1423-1433 https://doi.org/10.1038/sj.cdd.4401950
  8. Gorlach, A., P. Klappa, and T. Kietzmann. 2006. The endoplasmic reticulum: Folding, calcium homeostasis, signaling, and redox control. Antioxid. Redox Signal. 8: 1391-1418 https://doi.org/10.1089/ars.2006.8.1391
  9. Gray, C. W., R. V. Ward, E. Karran, S. Turconi, A. Rowles, D. Viglienghi, et al. 2000. Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response. Eur. J. Biochem. 267: 5699-5710 https://doi.org/10.1046/j.1432-1327.2000.01589.x
  10. Hacki, J., L. Egger, L. Monney, S. Conus, T. Rosse, I. Fellay, and C. Borner. 2000. Apoptotic crosstalk between the endoplasmic reticulum and mitochondria controlled by Bcl-2. Oncogene 19: 2286-2295 https://doi.org/10.1038/sj.onc.1203592
  11. Hegde, R., S. M. Srinivasula, Z. Zhang, R. Wassell, R. Mukattash, L. Cilenti, et al. 2002. Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J. Biol. Chem. 277: 432-438 https://doi.org/10.1074/jbc.M109721200
  12. Hori, O., F. Ichinoda, T. Tamatani, A. Yamaguchi, N. Sato, K. Ozawa, et al. 2002. Transmission of cell stress from endoplasmic reticulum to mitochondria: Enhanced expression of Lon protease. J. Cell Biol. 157: 1151-1160 https://doi.org/10.1083/jcb.200108103
  13. Jin, S., M. Kalkum, M. Overholtzer, A. Stoffel, B. T. Chait, and A. J. Levine. 2003. CIAP1 and the serine protease HTRA2 are involved in a novel p53-dependent apoptosis pathway in mammals. Genes Dev. 17: 359-367 https://doi.org/10.1101/gad.1047003
  14. Jones, J. M., P. Datta, S. M. Srinivasula, W. Ji, S. Gupta, Z. Zhang, et al. 2003. Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice. Nature 425: 721-727 https://doi.org/10.1038/nature02052
  15. Kaufman, R. J. 1999. Stress signaling from the lumen of the endoplasmic reticulum: Coordination of gene transcriptional and translational controls. Genes Dev. 13: 1211-1233 https://doi.org/10.1101/gad.13.10.1211
  16. Kaufman, R. J. 2002. Orchestrating the unfolded protein response in health and disease. J. Clin. Invest. 110: 1389-1398 https://doi.org/10.1172/JCI0216886
  17. Kobayashi, T., H. Sawa, J. Morikawa, S. Ueno, N. Katayama, W. Zhang, and H. Shiku. 2002. Bax-induction alone is sufficient to activate apoptosis cascade in wild-type Bax-bearing K562 cells, and the initiation of apoptosis requires simultaneous caspase activation. Int. J. Oncol. 20: 723-728
  18. Lindholm, D., H. Wootz, and L. Korhonen. 2006. ER stress and neurodegenerative diseases. Cell Death Differ. 13: 385-392 https://doi.org/10.1038/sj.cdd.4401778
  19. Ma, K., K. M. Vattem, and R. C. Wek. 2002. Dimerization and release of molecular chaperone inhibition facilitate activation of eukaryotic initiation factor-2 kinase in response to endoplasmic reticulum stress. J. Biol. Chem. 277: 18728-18735 https://doi.org/10.1074/jbc.M200903200
  20. Martins, L. M., I. Iaccarino, T. Tenev, S. Gschmeissner, N. F. Totty, N. R. Lemoine, et al. 2002. The serine protease Omi/ HtrA2 regulates apoptosis by binding XIAP through a reaperlike motif. J. Biol. Chem. 277: 439-444 https://doi.org/10.1074/jbc.M109784200
  21. Martins, L. M., A. Morrison, K. Klupsch, V. Fedele, N. Moisoi, P. Teismann, et al. 2004. Neuroprotective role of the reaperrelated serine protease HtrA2/Omi revealed by targeted deletion in mice. Mol. Cell. Biol. 24: 9848-9862 https://doi.org/10.1128/MCB.24.22.9848-9862.2004
  22. Nakagawa, T., H. Zhu, N. Morishima, E. Li, J. Xu, B. A. Yankner, and J. Yuan. 2000. Caspase-12 mediates endoplasmicreticulum- specific apoptosis and cytotoxicity by amyloid-beta. Nature 403: 98-103 https://doi.org/10.1038/47513
  23. Newmeyer, D. D. and S. Ferguson-Miller. 2003. Mitochondria: Releasing power for life and unleashing the machineries of death. Cell 112: 481-490 https://doi.org/10.1016/S0092-8674(03)00116-8
  24. No, D., T. P. Yao, and R. M. Evans. 1996. Ecdysone-inducible gene expression in mammalian cells and transgenic mice. Proc. Natl. Acad. Sci. USA 93: 3346-3351
  25. Park, J. H., D. H. Cho, C. W. Yun, J. W. Soh, Y. M. Jee, S. I. Park, I. Jo, and J. H. Nam. 2006. Role of protein kinase C $\delta$ in an early stage of coxsackievirus-B3-induced apoptosis in HeLa cells. J. Microbiol. Biotechnol. 16: 550-555
  26. Park, S. E., M. J. Lee, M. H. Yang, K. Y. Ahn, S. I. Jang, Y. J. Suh, H. Myung, J. C. You, and J. H. Park. 2007. Expression profiles and pathway analysis in HEK 293 T cells overexpressing HIV-1 Tat and nucleocapsid using cDNA microarray. J. Microbiol. Biotechnol. 17: 154-161
  27. Puthalakath, H., L. A. O'Reilly, P. Gunn, L. Lee, P. N. Kelly, N. D. Huntington, et al. 2007. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129: 1337-1349 https://doi.org/10.1016/j.cell.2007.04.027
  28. Rao, R. V. and D. E. Bredesen. 2004. Misfolded proteins, endoplasmic reticulum stress and neurodegeneration. Curr. Opin. Cell Biol. 16: 653-662
  29. Rideout, H. J., E. Zang, M. Yeasmin, R. Gordon, O. Jabado, D. S. Park, and L. Stefanis. 2001. Inhibitors of trypsin-like serine proteases prevent DNA damage-induced neuronal death by acting upstream of the mitochondrial checkpoint and of p53 induction. Neuroscience 107: 339-352 https://doi.org/10.1016/S0306-4522(01)00322-0
  30. Ruddock, L. W. and M. Molinari. 2006. N-Glycan processing in ER quality control. J. Cell Sci. 119: 4373-4380
  31. Saelens, X., N. Festjens, L. Vande Walle, M. van Gurp, G. van Loo, and P. Vandenabeele. 2004. Toxic proteins released from mitochondria in cell death. Oncogene 23: 2861-2874 https://doi.org/10.1038/sj.onc.1207523
  32. Seong, Y. M., J. Y. Choi, H. J. Park, K. J. Kim, S. G. Ahn, G. H. Seong, I. K. Kim, S. Kang, and H. Rhim. 2004. Autocatalytic processing of HtrA2/Omi is essential for induction of caspasedependent cell death through antagonizing XIAP. J. Biol. Chem. 279: 37588-37596 https://doi.org/10.1074/jbc.M401408200
  33. Shen, J., X. Chen, L. Hendershot, and R. Prywes. 2002. ER stress regulation of ATF6 localization by dissociation of BiP/ GRP78 binding and unmasking of Golgi localization signals. Dev. Cell 3: 99-111 https://doi.org/10.1016/S1534-5807(02)00203-4
  34. Sidrauski, C., R. Chapman, and P. Walter. 1998. The unfolded protein response: An intracellular signalling pathway with many surprising features. Trends Cell Biol. 8: 245-249 https://doi.org/10.1016/S0962-8924(98)01267-7
  35. Strauss, K. M., L. M. Martins, H. Plun-Favreau, F. P. Marx, S. Kautzmann, D. Berg, et al. 2005. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Hum. Mol. Genet. 14: 2099-2111 https://doi.org/10.1093/hmg/ddi215
  36. Suzuki, Y., Y. Imai, H. Nakayama, K. Takahashi, K. Takio, and R. Takahashi. 2001. A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol. Cell 8: 613-621 https://doi.org/10.1016/S1097-2765(01)00341-0
  37. Suzuki, Y., K. Takahashi-Niki, T. Akagi, T. Hashikawa, and R. Takahashi. 2004. Mitochondrial protease Omi/HtrA2 enhances caspase activation through multiple pathways. Cell Death Differ. 11: 208-216 https://doi.org/10.1038/sj.cdd.4401343
  38. Urano, F., A. Bertolotti, and D. Ron. 2000. IRE1 and efferent signaling from the endoplasmic reticulum. J. Cell Sci. 21: 3697-3702
  39. Uren, R. T., G. Dewson, C. Bonzon, T. Lithgow, D. D. Newmeyer, and R. M. Kluck. 2005. Mitochondrial release of pro-apoptotic proteins: Electrostatic interactions can hold cytochrome c but not Smac/DIABLO to mitochondrial membranes. J. Biol. Chem. 280: 2266-2274 https://doi.org/10.1074/jbc.M411106200
  40. van Loo, G., M. van Gurp, B. Depuydt, S. M. Srinivasula, I. Rodriguez, E. S. Alnemri, et al. 2002. The serine protease Omi/ HtrA2 is released from mitochondria during apoptosis. Omi interacts with caspase-inhibitor XIAP and induces enhanced caspase activity. Cell Death Differ. 9: 20-26 https://doi.org/10.1038/sj.cdd.4400970
  41. Verhagen, A. M., J. Silke, P. G. Ekert, M. Pakusch, H. Kaufmann, L. M. Connolly, et al. 2002. HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins. J. Biol. Chem. 277: 445-454 https://doi.org/10.1074/jbc.M109891200
  42. Wolf, B. B. and D. R. Green. 2002. Apoptosis: Letting slip the dogs of war. Curr. Biol. 12: 177-179 https://doi.org/10.1016/S0960-9822(02)00736-4
  43. Yamaguchi, H., K. Bhalla, and H. G. Wang. 2003. Bax plays a pivotal role in thapsigargin-induced apoptosis of human colon cancer HCT116 cells by controlling Smac/Diablo and Omi/ HtrA2 release from mitochondria. Cancer Res. 63: 1483-1489
  44. Yun, J., H.-Y. Chung, S.-J. Kim, H.-S. Cho, and J.-W. Oh. 2006. Purification and characterization of the functional catalytic domain of PKR-like endoplasmic reticulum kinase expressed in Escherichia coli. J. Microbiol. Biotechnol. 16: 1453-1458
  45. Zhao, L. and S. L. Ackerman. 2006. Endoplasmic reticulum stress in health and disease. Curr. Opin. Cell Biol. 18: 444-452 https://doi.org/10.1016/j.ceb.2006.06.005