Transglutaminase 2 inhibits apoptosis induced by calcium- overload through down-regulation of Bax.
An abrupt increase of intracellular Ca(2+) is observed in cells under hypoxic or oxidatively stressed conditions. The dysregulated increase of cytosolic Ca(2+) triggers apoptotic cell death through mitochondrial swelling and activation of Ca(2+)-dependent enzymes. Transglutaminase 2 (TG2) is a Ca(2+)-dependent enzyme that catalyzes transamidation reaction producing cross-linked and polyaminated proteins. TG2 activity is known to be involved in the apoptotic process. However, the pro-apoptotic role of TG2 is still controversial. In this study, we investigate the role of TG2 in apoptosis induced by Ca(2+)-overload. Overexpression of TG2 inhibited the A23187-induced apoptosis through suppression of caspase-3 and -9 activities, cytochrome c release into cytosol, and mitochondria membrane depolarization. Conversely, down-regulation of TG2 caused the increases of cell death, caspase-3 activity and cytochrome c in cytosol in response to Ca(2+)-overload. Western blot analysis of Bcl-2 family proteins showed that TG2 reduced the expression level of Bax protein. Moreover, overexpression of Bax abrogated the anti-apoptotic effect of TG2, indicating that TG2-mediated suppression of Bax is responsible for inhibiting cell death under Ca(2+)-overloaded conditions. Our findings revealed a novel anti-apoptotic pathway involving TG2, and suggested the induction of TG2 as a novel strategy for promoting cell survival in diseases such as ischemia and neurodegeneration.
Cho
Sung-Yup
SY
Department of Biochemistry and Molecular Biology/Aging and Apoptosis Research Center (AARC), Seoul National University College of Medicine, Seoul 110-799, Korea.
Lee
Jin-Haeng
JH
Bae
Han-Dong
HD
Jeong
Eui Man
EM
Jang
Gi-Yong
GY
Kim
Chai-Wan
CW
Shin
Dong-Myung
DM
Jeon
Ju-Hong
JH
Kim
In-Gyu
IG
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002470:Cell Survival; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation; D019204:GTP-Binding Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; D007476:Ionophores; D051028:bcl-2-Associated X Protein; D000001:Calcimycin; D045304:Cytochromes c; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D020169:Caspases; D019204:GTP-Binding Proteins; D002118:Calcium