Mature T-lymphocytes undergo spontaneous apoptosis in the biobreeding diabetes-prone strain of rats due to the loss of the functional GIMAP5 (GTPase of the immune-associated nucleotide-binding protein 5) protein. The mechanisms underlying the pro-survival function of GIMAP5 in T-cells have not yet been elucidated. We have previously shown that GIMAP5 deficiency in T-cells impairs Ca2+ entry via plasma membrane channels following exposure to thapsigargin or stimulation of the T-cell antigen receptor. In the present study we report that this reduced Ca2+ influx in GIMAP5-deficient T-cells is associated with the inability of their mitochondria to sequester Ca2+ following capacitative entry, which is required for sustained Ca2+ influx via the plasma membrane channels. Consistent with a role for GIMAP5 in regulating mitochondrial Ca2+, overexpression of GIMAP5 in HEK (human embryonic kidney)-293 cells resulted in increased Ca2+ accumulation within the mitochondria. Disruption of microtubules, but not the actin cytoskeleton, abrogated mitochondrial Ca2+ sequestration in primary rat T-cells, whereas both microtubules and actin cytoskeleton were needed for the GIMAP5-mediated increase in mitochondrial Ca2+ in HEK-293 cells. Moreover, GIMAP5 showed partial colocalization with tubulin in HEK-293 cells. On the basis of these findings, we propose that the pro-survival function of GIMAP5 in T-lymphocytes may be linked to its requirement to facilitate microtubule-dependent mitochondrial buffering of Ca2+ following capacitative entry.
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Research Article|
December 14 2012
GTPase of the immune-associated nucleotide-binding protein 5 (GIMAP5) regulates calcium influx in T-lymphocytes by promoting mitochondrial calcium accumulation
Xi Lin Chen;
Xi Lin Chen
*Immunology division, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4
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Daniel Serrano;
Daniel Serrano
*Immunology division, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4
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Marian Mayhue;
Marian Mayhue
*Immunology division, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4
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Hans-Joachim Wieden;
Hans-Joachim Wieden
†Department of Chemistry and Biochemistry, University of Lethbridge, Lethbridge, Alberta, Canada T1K 3M4
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Jana Stankova;
Jana Stankova
*Immunology division, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4
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Guylain Boulay;
Guylain Boulay
‡Department of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4
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Subburaj Ilangumaran;
Subburaj Ilangumaran
*Immunology division, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4
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Sheela Ramanathan
Sheela Ramanathan
1
§Centre de Recherche Clinique Etienne-Le Bel, Centre Hospitalier de l’Université de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4
1To whom correspondence should be addressed (email sheela.ramanathan@usherbrooke.ca).
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Publisher: Portland Press Ltd
Received:
March 29 2012
Revision Received:
October 17 2012
Accepted:
October 26 2012
Accepted Manuscript online:
October 26 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem J (2013) 449 (2): 353–364.
Article history
Received:
March 29 2012
Revision Received:
October 17 2012
Accepted:
October 26 2012
Accepted Manuscript online:
October 26 2012
Citation
Xi Lin Chen, Daniel Serrano, Marian Mayhue, Hans-Joachim Wieden, Jana Stankova, Guylain Boulay, Subburaj Ilangumaran, Sheela Ramanathan; GTPase of the immune-associated nucleotide-binding protein 5 (GIMAP5) regulates calcium influx in T-lymphocytes by promoting mitochondrial calcium accumulation. Biochem J 15 January 2013; 449 (2): 353–364. doi: https://doi.org/10.1042/BJ20120516
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