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

PLoS One. 2013 Dec 11;8(12):e81516. doi: 10.1371/journal.pone.0081516. eCollection 2013.

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 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.

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • Calcium / metabolism*
  • Calcium Signaling*
  • Cell Line
  • Endoplasmic Reticulum / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • GTP-Binding Proteins
  • Gene Expression Regulation
  • Guanine Nucleotide Exchange Factors / genetics*
  • Guanine Nucleotide Exchange Factors / metabolism
  • Homeostasis
  • Humans
  • Inositol Phosphates / metabolism
  • Ion Transport
  • Jurkat Cells
  • Mice
  • Mitochondria / metabolism
  • Protein Glutamine gamma Glutamyltransferase 2
  • Ryanodine Receptor Calcium Release Channel / genetics
  • Ryanodine Receptor Calcium Release Channel / metabolism
  • Transglutaminases / genetics*
  • Transglutaminases / metabolism

Substances

  • Guanine Nucleotide Exchange Factors
  • Inositol Phosphates
  • RAP1GDS1 protein, human
  • Ryanodine Receptor Calcium Release Channel
  • inositol 3-phosphate
  • Protein Glutamine gamma Glutamyltransferase 2
  • Transglutaminases
  • GTP-Binding Proteins
  • Calcium