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- Title
Transglutaminase 2 Contributes to Apoptosis Induction in Jurkat T Cells by Modulating Ca<sup>2+</sup> Homeostasis via Cross-Linking RAP1GDS1.
- Authors
Hsieh, Yu-Fan; Liu, Guang-Yaw; Lee, Yi-Ju; Yang, Jiann-Jou; Sándor, Katalin; Sarang, Zsolt; Bononi, Angela; Pinton, Paolo; Tretter, László; Szondy, Zsuzsa; Tsay, Gregory J.
- Abstract
Background: Transglutaminase 2 (TG2) is a protein cross-linking enzyme known to be associated with the in vivo apoptosis program of T cells. However, its role in the T cell apoptosis program was not investigated yet. Results: Here we report that timed overexpression of both the wild type (wt) and the cross-linking mutant of TG2 induced apoptosis in Jurkat T cells, the wt being more effective. Part of TG2 colocalised with mitochondria. WtTG2-induced apoptosis was characterized by enhanced mitochondrial Ca2+ uptake. Ca2+-activated wtTG2 cross-linked RAP1, GTP-GDP dissociation stimulator 1, an unusual guanine exchange factor acting on various small GTPases, to induce a yet uncharacterized signaling pathway that was able to promote the Ca2+ release from the endoplasmic reticulum via both Ins3P and ryanodine sensitive receptors leading to a consequently enhanced mitochondrial Ca2+uptake. Conclusions: Our data indicate that TG2 might act as a Ca2+ sensor to amplify endoplasmic reticulum-derived Ca2+ signals to enhance mitochondria Ca2+ uptake. Since enhanced mitochondrial Ca2+ levels were previously shown to sensitize mitochondria for various apoptotic signals, our data demonstrate a novel mechanism through which TG2 can contribute to the induction of apoptosis in certain cell types. Since, as compared to knock out cells, physiological levels of TG2 affected Ca2+ signals in mouse embryonic fibroblasts similar to Jurkat cells, our data might indicate a more general role of TG2 in the regulation of mitochondrial Ca2+ homeostasis.
- Subjects
TRANSGLUTAMINASES; APOPTOSIS; PROTEIN crosslinking; GENETIC mutation; PHYSIOLOGICAL effects of calcium; MITOCHONDRIAL enzymes; CELLULAR signal transduction; GUANOSINE triphosphatase
- Publication
PLoS ONE, 2013, Vol 8, Issue 12, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0081516