Journal
PLOS ONE
Volume 8, Issue 12, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0081516
Keywords
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Categories
Funding
- National Science Council (NSC) [NSC 95-2745-B-040-007, NSC 96-2314-B-040-013-MY3, NSC97-29111-I-040-001, NSC 96-2911-I-040-002, NSC98-2811-B-040-004, NS99-2314-B-040-006-MY3, NSC99-2911-I-040-001, NSC 99-2811-B-040-005]
- Chung Shan Medical University Hospital grand [CSH-2010-D-2002, CSH-2012-D-001]
- Hungarian National Research Fund [OTKA K 77587, 83865, 104228, NK105046]
- European Social Fund
- European Regional Development Fund
- Hungarian Taiwanese bilateral agreement
- Italian Association for Cancer Research (AIRC)
- Telethon [GGP09128, GGP11139B]
- University of Ferrara
- Italian Ministry of Education, University and Research (COFIN)
- Italian Ministry of Education, University and Research (FIRB)
- Italian Ministry of Education, University and Research (Futuro in Ricerca)
- Italian Ministry of Health
- [TAMOP 4.2.2. A-11/1/KONV-2012-0023]
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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 Ins(3)P 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.
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