Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
권호 표지
DOI QR코드

DOI QR Code

Mitochondrial Targeting Domain Homologs Induce Necrotic Cell Death Via Mitochondrial and Endoplasmic Reticulum Disruption

  • Park, Junghee (Department of Biochemistry and Molecular Biology, Chosun University School of Medicine) ;
  • Han, Ji-Hye (Department of Biochemistry and Molecular Biology, Chosun University School of Medicine) ;
  • Myung, Seung-Hyun (Department of Biochemistry and Molecular Biology, Chosun University School of Medicine) ;
  • Chung, Hea-jong (Gwangju Center, Korea Basic Science Institute) ;
  • Park, Jae-il (Gwangju Center, Korea Basic Science Institute) ;
  • Cho, Ju-Yeon (Department of Medicine, Chosun University Hospital) ;
  • Kim, Tae-Hyoung (Department of Biochemistry and Molecular Biology, Chosun University School of Medicine)
  • Received : 2021.04.14
  • Accepted : 2021.05.18
  • Published : 2021.06.28
Download PDF
⟨ Previous Next ⟩

Abstract

The mitochondrial targeting domain (MTD) of Noxa contributes to its mitochondrial localization and to apoptosis induction. As a peptide, MTD fused with octa-arginine (R8), a CPP, induces necrosis related to intracellular calcium influx and destruction of mitochondria and endoplasmic reticulum. We searched for homologs of MTD, and compared their cell killing capability when fused with R8. Three of the seven peptides triggered cell death with similar mechanisms. The comparative analysis of peptide sequences showed that four amino acid sites of MTD are critical in regulating necrosis, suggesting the potential to generate artificial, adjustable cytotoxic peptides, which could be effective medicines for many diseases. Thus, homologs functionality could hint to the functions of their belonging proteins.

Keywords

Acknowledgement

This study was supported by funding from Chosun University, 2020.

References

  1. Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, et al. 2000. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science (New York, NY.) 288: 1053-1058. https://doi.org/10.1126/science.288.5468.1053
  2. Seo YW, Shin JN, Ko KH, Cha JH, Park JY, Lee BR, et al. 2003. The molecular mechanism of Noxa-induced mitochondrial dysfunction in p53-mediated cell death. J. Biol. Chem. 278: 48292-48299. https://doi.org/10.1074/jbc.M308785200
  3. Guikema JE, Amiot M, Eldering E. 2017. Exploiting the pro-apoptotic function of NOXA as a therapeutic modality in cancer. Expert. Opin. Ther. Targets 21: 767-779. https://doi.org/10.1080/14728222.2017.1349754
  4. Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T, et al. 2001. BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol. Cell 8: 705-711. https://doi.org/10.1016/S1097-2765(01)00320-3
  5. Tait SW, Green DR. 2013. Mitochondrial regulation of cell death. Cold Spring Harb. Perspect. Biol. 5: a008706. https://doi.org/10.1101/cshperspect.a008706
  6. Han JH, Park J, Myung SH, Lee SH, Kim HY, Kim KS, et al. 2019. Noxa mitochondrial targeting domain induces necrosis via VDAC2 and mitochondrial catastrophe. Cell Death Dis. 10: 519. https://doi.org/10.1038/s41419-019-1753-4
  7. Park J, Han JH, Myung SH, Kang H, Cho JY, Kim TH. 2019. A peptide containing Noxa mitochondrial-targeting domain induces cell death via mitochondrial and endoplasmic reticulum disruption. Biochem. Biophy. Res. Commun. 518: 80-86. https://doi.org/10.1016/j.bbrc.2019.08.011
  8. Park J, Han JH, Myung SH, Kim TH. 2020. Isothiocyanate groups of 4,4'-diisothiocyanatostilbene-2,2'-disulfonate (DIDS) inhibit cell penetration of octa-arginine (R8)-fused peptides. J. Pept. Sci. 26: e3237. https://doi.org/10.1002/psc.3237
  9. Seo YW, Woo HN, Piya S, Moon AR, Oh JW, Yun CW, et al. 2009. The cell death-inducing activity of the peptide containing Noxa mitochondrial-targeting domain is associated with calcium release. Cancer Res. 69: 8356-8365. https://doi.org/10.1158/0008-5472.CAN-09-0349
  10. Woo HN, Seo YW, Moon AR, Jeong SY, Jeong SY, Choi EK, et al. 2009. Effects of the BH3-only protein human Noxa on mitochondrial dynamics. FEBS Lett. 583: 2349-2354. https://doi.org/10.1016/j.febslet.2009.06.029
  11. Park J, Han JH, Myung SH, Seo YW, Kim TH. 2018. MTD-like motif of a BH3-only protein, BNIP1, induces necrosis accompanied by an intracellular calcium spike. Biochem. Biophys. Res. Commun. 495: 1661-1667. https://doi.org/10.1016/j.bbrc.2017.12.022
  12. Boyd JM, Malstrom S, Subramanian T, Venkatesh LK, Schaeper U, Elangovan B, et al. 1994. Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins. Cell 79: 341-351. https://doi.org/10.1016/0092-8674(94)90202-X
  13. Zhang H, Heim J, Meyhack B. 1999. Novel BNIP1 variants and their interaction with BCL2 family members. FEBS Lett. 448: 23-27. https://doi.org/10.1016/S0014-5793(99)00335-X
  14. Ryu SW, Choi K, Yoon J, Kim S, Choi C. 2012. Endoplasmic reticulum-specific BH3-only protein BNIP1 induces mitochondrial fragmentation in a Bcl-2- and Drp1-dependent manner. J. Cell. Physiol. 227: 3027-3035. https://doi.org/10.1002/jcp.23044
  15. Melikov K, Hara A, Yamoah K, Zaitseva E, Zaitsev E, Chernomordik LV. 2015. Efficient entry of cell-penetrating peptide nona-arginine into adherent cells involves a transient increase in intracellular calcium. Biochem. J. 471: 221-230. https://doi.org/10.1042/BJ20150272