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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 Ca 2+  uptake. Ca 2+ -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 Ca 2+  release from the endoplasmic reticulum via both Ins 3 P and ryanodine sensitive receptors leading to a consequently enhanced mitochondrial Ca 2+ uptake.    Conclusions  Our data indicate that TG2 might act as a Ca 2+  sensor to amplify endoplasmic reticulum-derived Ca 2+  signals to enhance mitochondria Ca 2+  uptake. Since enhanced mitochondrial Ca 2+  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 Ca 2+  signals in mouse embryonic fibroblasts similar to Jurkat cells, our data might indicate a more general role of TG2 in the regulation of mitochondrial Ca 2+  homeostasis.

Transglutaminase 2 Contributes to Apoptosis Induction in Jurkat T Cells by Modulating Ca2+ Homeostasis via Cross-Linking RAP1GDS1