GTPase of the immune-associated nucleotide-binding protein 5 (GIMAP5) regulates calcium influx in T-lymphocytes by promoting mitochondrial calcium accumulation

Biochemical Journal (Impact Factor: 4.4). 10/2012; 449(2). DOI: 10.1042/BJ20120516
Source: PubMed


Mature T lymphocytes undergo spontaneous apoptosis in the biobreeding diabetes-prone strain of rats due to the loss of functional GIMAP5 (GTPase of the immune-associated nucleotide binding protein 5) protein. 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 calcium entry via plasma membrane channels following exposure to thapsigargin, or stimulation of the T cell antigen receptor. Here we report that this reduced Ca2+ influx in GIMAP5 deficient T cells is associated with the inability of their mitochondria to sequester calcium 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 HEK293 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 HEK293 cells. Moreover, GIMAP5 showed partial colocalization with tubulin in HEK293 cells. Based on 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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Available from: Sheela Ramanathan, Jan 26, 2015
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