title: Transglutaminase 2 contributes to apoptosis induction in Jurkat T cells by modulating Ca2+ 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 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.
authors.affiliation: Institute of Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Yu-Fan
authors.initials: YF
authors.lastname: Hsieh
authors.affiliation: Institute of Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Guang-Yaw
authors.initials: GY
authors.lastname: Liu
authors.affiliation: Institute of Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Yi-Ju
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Jiann-Jou
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, Research Center of Molecular Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Sándor
authors.affiliation: Department of Biochemistry and Molecular Biology, Research Center of Molecular Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Sarang
authors.affiliation: Department of Experimental and Diagnostic Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation (ICSI), Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Bononi
authors.affiliation: Department of Experimental and Diagnostic Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation (ICSI), Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pinton
authors.affiliation: Department of Medical Biochemistry, Semmelweis University, Neurobiochemical Group of Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Tretter
authors.affiliation: Department of Biochemistry and Molecular Biology, Research Center of Molecular Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Szondy
authors.affiliation: Institute of Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan ; Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tsay
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D019204:GTP-Binding Proteins; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D017136:Ion Transport; D019169:Jurkat Cells; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism; D011503:Transglutaminases / Q000235:genetics* / Q000378:metabolism
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D007295:Inositol Phosphates; C115955:RAP1GDS1 protein, human; D019837:Ryanodine Receptor Calcium Release Channel; C052128:inositol 3-phosphate; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D002118:Calcium