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

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 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 ₃P 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.