Transglutaminase 2 contributes to apoptosis induction in jurkat t cells by modulating Ca2+ homeostasis via cross-linking RAP1GDS1

Yu Fan Hsieh, Guang Yaw Liu, Yi Ju Lee, Jiann Jou Yang, Katalin Sándor, Zsolt Sarang, Angela Bononi, Paolo Pinton, László Tretter, Zsuzsa Szondy, Gregory J. Tsay

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11 Citations (Scopus)

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.

Original languageEnglish
Article numbere81516
JournalPloS one
Volume8
Issue number12
DOIs
Publication statusPublished - Dec 11 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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