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TGFβ mediates activation of transglutaminase 2 in response to oxidative stress that leads to protein aggregation

Dong-Myung Shin^*, Ju-Hong Jeon, Chai-Wan Kim^*, Sung-Yup Cho^*, Hye-Jin Lee^*, Gi-Yong Jang^*, Eui Man Jeong^*, Dong-Sup Lee, Ja-Heon Kang, Gerry Melino^||, Sang-Chul Park^* and In-Gyu Kim^*,1

^* Department of Biochemistry and Molecular Biology/Aging and Apoptosis Research Center (AARC),

Department of Physiology and Biophysics, and

Cancer Research Institute, Seoul National University College of Medicine, Seoul Korea;

Department of Ophthalmology, Kyung Hee University College of Medicine, Seoul, Korea; and

^|| Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy

¹Correspondence: Department of Biochemistry and Molecular Biology/AARC, Seoul National University College of Medicine, 28 Yongon Dong, Chongno Gu, Seoul 110–799, Korea. E-mail: igkim{at}plaza.snu.ac.kr

Transglutaminase 2 (TGase2) is a ubiquitously expressed enzyme that catalyzes irreversible post-translational modification of protein, forming cross-linked protein aggregates. We previously reported that intracellular TGase2 is activated by oxidative stress. To elucidate the functional role of TGase2 activation in cells under the oxidatively stressed condition, we identified the mediator that activates TGase2. In this study, we showed that low levels of oxidative stress trigger the release of TGFβ, which subsequently activates TGase2 through the nuclear translocation of Smad3. Analysis of substrate proteins reveals that TGase2-mediated protein modification results in a decrease of protein solubility and a collapse of intermediate filament network, which leads to aggregation of proteins. We confirm these results using lens tissues from TGase2-deficient mice. Among several antioxidants tried, only N-acetylcysteine effectively inhibits TGFβ-mediated activation of TGase2. These results indicate that TGFβ mediates oxidative stress-induced protein aggregation through activation of TGase2 and suggest that the formation of protein aggregation may not be a passive process of self-assembly of oxidatively damaged proteins but may be an active cellular response to oxidative stress. Therefore, TGFβ-TGase2 pathway may have implications for both the pathogenesis of age-related degenerative diseases and the development of pharmaceutics.—Shin, D.-M., Jeon, J.-H. Kim, C.-W., Cho, S.-Y., Lee, H.-J., Jang, G.-Y., Jeong, E. M., Lee, D.-S., Kang, J.-H., Melino, G., Park, S.-C., Kim, I.-G. TGFβ mediates activation of transglutaminase 2 in response to oxidative stress that leads to protein aggregation.

Key Words: aging • cataract • protein modification