title: GTPase of the immune-associated nucleotide-binding protein 5 (GIMAP5) regulates calcium influx in T-lymphocytes by promoting mitochondrial calcium accumulation.
abstract: 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.
authors.affiliation: Immunology division, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4.
authors.forename: Xi Lin
authors.initials: XL
authors.lastname: Chen
authors.forename: Daniel
authors.initials: D
authors.lastname: Serrano
authors.forename: Marian
authors.initials: M
authors.lastname: Mayhue
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Wieden
authors.forename: Jana
authors.initials: J
authors.lastname: Stankova
authors.forename: Guylain
authors.initials: G
authors.lastname: Boulay
authors.forename: Subburaj
authors.initials: S
authors.lastname: Ilangumaran
authors.forename: Sheela
authors.initials: S
authors.lastname: Ramanathan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D017136:Ion Transport; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism
chemical_list: C484030:GIMAP5 protein, human; D011948:Receptors, Antigen, T-Cell; D014404:Tubulin; D019204:GTP-Binding Proteins; C494977:Gimap5 protein, rat; D002118:Calcium