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

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 Ins3P 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.