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2014-April Volume 33 Issue 4

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Endoplasmic reticulum stress activates transglutaminase 2 leading to protein aggregation

  • Authors:
    • Jin-Haeng Lee
    • Jaeho Jeong
    • Eui Man Jeong
    • Sung-Yup Cho
    • Jeong Wook Kang
    • Jisun Lim
    • Jinbeom Heo
    • Hyunsook Kang
    • In-Gyu Kim
    • Dong-Myung Shin
  • View Affiliations / Copyright

    Affiliations: Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea, Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
    Copyright: © Lee et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].
  • Pages: 849-855
    |
    Published online on: January 30, 2014
       https://doi.org/10.3892/ijmm.2014.1640
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Abstract

Aberrant activation of transglutaminase 2 (TGase2) contributes to a variety of protein conformational disorders such as neurodegenerative diseases and age-related cataracts. The accumulation of improperly folded proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), which promotes either repair or degradation of the damaged proteins. Inadequate UPR results in protein aggregation that may contribute to the development of age-related degenerative diseases. TGase2 is a calcium-dependent enzyme that irreversibly modifies proteins by forming cross-linked protein aggregates. Intracellular TGase2 is activated by oxidative stress which generates large quantities of unfolded proteins. However, the relationship between TGase2 activity and UPR has not yet been established. In the present study, we demonstrated that ER stress activated TGase2 in various cell types. TGase2 activation was dependent on the ER stress-induced increase in the intracellular calcium ion concentration but not on the TGase2 protein expression level. Enzyme substrate analysis revealed that TGase2-mediated protein modification promoted protein aggregation concurrently with decreasing water solubility. Moreover, treatment with KCC009, a TGase2 inhibitor, abrogated ER stress-induced TGase2 activation and subsequent protein aggregation. However, TGase2 activation had no effect on ER stress-induced cell death. These results demonstrate that the accumulation of misfolded proteins activates TGase2, which further accelerates the formation of protein aggregates. Therefore, we suggest that inhibition of TGase2 may be a novel strategy by which to prevent the protein aggregation in age-related degenerative diseases.
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1 

Hartl FU, Bracher A and Hayer-Hartl M: Molecular chaperones in protein folding and proteostasis. Nature. 475:324–332. 2011. View Article : Google Scholar : PubMed/NCBI

2 

Lin MT and Beal MF: Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 443:787–795. 2006. View Article : Google Scholar : PubMed/NCBI

3 

Bence NF, Sampat RM and Kopito RR: Impairment of the ubiquitin-proteasome system by protein aggregation. Science. 292:1552–1555. 2001. View Article : Google Scholar : PubMed/NCBI

4 

Lorand L and Graham RM: Transglutaminases: crosslinking enzymes with pleiotropic functions. Nat Rev Mol Cell Biol. 4:140–156. 2003. View Article : Google Scholar : PubMed/NCBI

5 

Klöck C and Khosla C: Regulation of the activities of the mammalian transglutaminase family of enzymes. Protein Sci. 21:1781–1791. 2012.PubMed/NCBI

6 

Prasanna Murthy SN, Velasco PT and Lorand L: Properties of purified lens transglutaminase and regulation of its transamidase/crosslinking activity by GTP. Exp Eye Res. 67:273–281. 1998.PubMed/NCBI

7 

Jeitner TM, Bogdanov MB, Matson WR, et al: Nɛ-(γ-l-Glutamyl)-l-lysine (GGEL) is increased in cerebrospinal fluid of patients with Huntington’s disease. J Neurochem. 79:1109–1112. 2001.

8 

Konno T, Morii T, Hirata A, Sato S, Oiki S and Ikura K: Covalent blocking of fibril formation and aggregation of intracellular amyloidgenic proteins by transglutaminase-catalyzed intramolecular cross-linking. Biochemistry. 44:2072–2079. 2005. View Article : Google Scholar

9 

Halverson RA, Lewis J, Frausto S, Hutton M and Muma NA: Tau protein is cross-linked by transglutaminase in P301L tau transgenic mice. J Neurosci. 25:1226–1233. 2005. View Article : Google Scholar : PubMed/NCBI

10 

Shin DM, Jeon JH, Kim CW, et al: Cell type-specific activation of intracellular transglutaminase 2 by oxidative stress or ultraviolet irradiation: implications of transglutaminase 2 in age-related cataractogenesis. J Biol Chem. 279:15032–15039. 2004. View Article : Google Scholar

11 

Shin D-M, Jeon J-H, Kim C-W, et al: TGFβ mediates activation of transglutaminase 2 in response to oxidative stress that leads to protein aggregation. FASEB J. 22:2498–2507. 2008.

12 

Moore KA and Hollien J: The unfolded protein response in secretory cell function. Annu Rev Genet. 46:165–183. 2012. View Article : Google Scholar : PubMed/NCBI

13 

Lin JH, Walter P and Yen TS: Endoplasmic reticulum stress in disease pathogenesis. Annu Rev Pathol. 3:399–425. 2008. View Article : Google Scholar

14 

Schröder M and Kaufman RJ: The mammalian unfolded protein response. Annu Rev Biochem. 74:739–789. 2005.

15 

Xin W, Li X, Lu X, Niu K and Cai J: Involvement of endoplasmic reticulum stress-associated apoptosis in a heart failure model induced by chronic myocardial ischemia. Int J Mol Med. 27:503–509. 2011.PubMed/NCBI

16 

Wu LF, Wei BL, Guo YT, et al: Apoptosis induced by adenosine involves endoplasmic reticulum stress in EC109 cells. Int J Mol Med. 30:797–804. 2012.PubMed/NCBI

17 

Harding HP, Zhang Y, Zeng H, et al: An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell. 11:619–633. 2003. View Article : Google Scholar : PubMed/NCBI

18 

Cho S-Y, Lee J-H, Bae H-D, et al: Transglutaminase 2 inhibits apoptosis induced by calcium overload through down-regulation of Bax. Exp Mol Med. 42:639–650. 2010. View Article : Google Scholar : PubMed/NCBI

19 

Jang GY, Jeon JH, Cho SY, et al: Transglutaminase 2 suppresses apoptosis by modulating caspase 3 and NF-kappaB activity in hypoxic tumor cells. Oncogene. 29:356–367. 2009. View Article : Google Scholar : PubMed/NCBI

20 

Choi K, Siegel M, Piper JL, et al: Chemistry and biology of dihydroisoxazole derivatives: selective inhibitors of human transglutaminase 2. Chem Biol. 12:469–475. 2005. View Article : Google Scholar : PubMed/NCBI

21 

Jeon JH, Choi KH, Cho SY, et al: Transglutaminase 2 inhibits Rb binding of human papillomavirus E7 by incorporating polyamine. EMBO J. 22:5273–5282. 2003. View Article : Google Scholar : PubMed/NCBI

22 

Fesus L and Piacentini M: Transglutaminase 2: an enigmatic enzyme with diverse functions. Trends Biochem Sci. 27:534–539. 2002. View Article : Google Scholar : PubMed/NCBI

23 

Caccamo D, Condello S, Ferlazzo N, Currò M, Griffin M and Ientile R: Transglutaminase 2 interaction with small heat shock proteins mediate cell survival upon excitotoxic stress. Amino Acids. 44:151–159. 2013. View Article : Google Scholar : PubMed/NCBI

24 

Kweon SM, Lee ZW, Yi SJ, et al: Protective role of tissue transglutaminase in the cell death induced by TNF-alpha in SH-SY5Y neuroblastoma cells. J Biochem Mol Biol. 37:185–191. 2004. View Article : Google Scholar : PubMed/NCBI

25 

Wakshlag JJ, Antonyak MA, Boehm JE, Boehm K and Cerione RA: Effects of tissue transglutaminase on beta-amyloid1–42-induced apoptosis. Protein J. 25:83–94. 2006.PubMed/NCBI

26 

Candi E, Schmidt R and Melino G: The cornified envelope: a model of cell death in the skin. Nat Rev Mol Cell Biol. 6:328–340. 2005. View Article : Google Scholar : PubMed/NCBI

27 

Muszbek L, Bereczky Z, Bagoly Z, Komáromi I and Katona É: Factor XIII: a coagulation factor with multiple plasmatic and cellular functions. Physiol Rev. 91:931–972. 2011. View Article : Google Scholar : PubMed/NCBI

28 

Mukherjee DC, Agrawal AK, Manjunath R and Mukherjee AB: Suppression of epididymal sperm antigenicity in the rabbit by uteroglobin and transglutaminase in vitro. Science. 219:989–991. 1983. View Article : Google Scholar : PubMed/NCBI

29 

Lee S-M, Jeong EM, Jeong J, et al: Cysteamine prevents the development of lens opacity in a rat model of selenite-induced cataract. Invest Ophthalmol Vis Sci. 53:1452–1459. 2012. View Article : Google Scholar : PubMed/NCBI

30 

Király R, Demény M and Fésüs L: Protein transamidation by transglutaminase 2 in cells: a disputed Ca2+-dependent action of a multifunctional protein. FEBS J. 278:4717–4739. 2011.PubMed/NCBI

31 

Sue Menko A: Lens epithelial cell differentiation. Exp Eye Res. 75:485–490. 2002.PubMed/NCBI

32 

Junn E, Ronchetti RD, Quezado MM, Kim SY and Mouradian MM: Tissue transglutaminase-induced aggregation of alpha-synuclein: implications for Lewy body formation in Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci USA. 100:2047–2052. 2003.PubMed/NCBI

33 

Karpuj MV, Becher MW, Springer JE, et al: Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine. Nat Med. 8:143–149. 2002. View Article : Google Scholar : PubMed/NCBI

34 

Mastroberardino PG, Iannicola C, Nardacci R, et al: ‘Tissue’ transglutaminase ablation reduces neuronal death and prolongs survival in a mouse model of Huntington’s disease. Cell Death Differ. 9:873–880. 2002.

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Copy and paste a formatted citation
Spandidos Publications style
Lee J, Jeong J, Jeong EM, Cho S, Kang JW, Lim J, Heo J, Kang H, Kim I, Shin D, Shin D, et al: Endoplasmic reticulum stress activates transglutaminase 2 leading to protein aggregation . Int J Mol Med 33: 849-855, 2014.
APA
Lee, J., Jeong, J., Jeong, E.M., Cho, S., Kang, J.W., Lim, J. ... Shin, D. (2014). Endoplasmic reticulum stress activates transglutaminase 2 leading to protein aggregation . International Journal of Molecular Medicine, 33, 849-855. https://doi.org/10.3892/ijmm.2014.1640
MLA
Lee, J., Jeong, J., Jeong, E. M., Cho, S., Kang, J. W., Lim, J., Heo, J., Kang, H., Kim, I., Shin, D."Endoplasmic reticulum stress activates transglutaminase 2 leading to protein aggregation ". International Journal of Molecular Medicine 33.4 (2014): 849-855.
Chicago
Lee, J., Jeong, J., Jeong, E. M., Cho, S., Kang, J. W., Lim, J., Heo, J., Kang, H., Kim, I., Shin, D."Endoplasmic reticulum stress activates transglutaminase 2 leading to protein aggregation ". International Journal of Molecular Medicine 33, no. 4 (2014): 849-855. https://doi.org/10.3892/ijmm.2014.1640
Copy and paste a formatted citation
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Spandidos Publications style
Lee J, Jeong J, Jeong EM, Cho S, Kang JW, Lim J, Heo J, Kang H, Kim I, Shin D, Shin D, et al: Endoplasmic reticulum stress activates transglutaminase 2 leading to protein aggregation . Int J Mol Med 33: 849-855, 2014.
APA
Lee, J., Jeong, J., Jeong, E.M., Cho, S., Kang, J.W., Lim, J. ... Shin, D. (2014). Endoplasmic reticulum stress activates transglutaminase 2 leading to protein aggregation . International Journal of Molecular Medicine, 33, 849-855. https://doi.org/10.3892/ijmm.2014.1640
MLA
Lee, J., Jeong, J., Jeong, E. M., Cho, S., Kang, J. W., Lim, J., Heo, J., Kang, H., Kim, I., Shin, D."Endoplasmic reticulum stress activates transglutaminase 2 leading to protein aggregation ". International Journal of Molecular Medicine 33.4 (2014): 849-855.
Chicago
Lee, J., Jeong, J., Jeong, E. M., Cho, S., Kang, J. W., Lim, J., Heo, J., Kang, H., Kim, I., Shin, D."Endoplasmic reticulum stress activates transglutaminase 2 leading to protein aggregation ". International Journal of Molecular Medicine 33, no. 4 (2014): 849-855. https://doi.org/10.3892/ijmm.2014.1640
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