TGFbeta mediates activation of transglutaminase 2 in response to oxidative stress that leads to protein aggregation.
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 TGFbeta, 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 TGFbeta-mediated activation of TGase2. These results indicate that TGFbeta 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, TGFbeta-TGase2 pathway may have implications for both the pathogenesis of age-related degenerative diseases and the development of pharmaceutics.
Shin
Dong-Myung
DM
Department of Biochemistry and Molecular Biology/AARC, Seoul National University College of Medicine, 28 Yongon Dong, Chongno Gu, Seoul 110-799, Korea.
Jeon
Ju-Hong
JH
Kim
Chai-Wan
CW
Cho
Sung-Yup
SY
Lee
Hye-Jin
HJ
Jang
Gi-Yong
GY
Jeong
Eui Man
EM
Lee
Dong-Sup
DS
Kang
Ja-Heon
JH
Melino
Gerry
G
Park
Sang-Chul
SC
Kim
In-Gyu
IG
D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007908:Lens, Crystalline / Q000187:drug effects / Q000201:enzymology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D011503:Transglutaminases / Q000187:drug effects / Q000378:metabolism*
D016212:Transforming Growth Factor beta; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D002118:Calcium