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Modulation of T Cell Metabolism and Function through Calcium Signaling.

Fracchia KM, Pai CY, Walsh CM - Front Immunol (2013)

Bottom Line: While Ca(2+) is known to modulate T cell activation via effects on calcineurin and its target, nuclear factor of activated T cells (NFAT), this second messenger also regulates other pathways, including protein kinase C, calmodulin kinases, and cytoskeletal proteins.As a target of mitochondrial ROS and Ca(2+) regulation, we describe the involvement of the serine/threonine kinase DRAK2 in the context of these processes.Given the important roles for Ca(2+) dependent signaling and cellular metabolism in adaptive immune responses, the crosstalk between these pathways is likely to be important for the regulation of T cell activation, tolerance, and homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology and Biochemistry, The Institute for Immunology, University of California Irvine , Irvine, CA , USA.

ABSTRACT
As a vital second messenger in the activation of lymphocytes, the divalent cation Ca(2+) plays numerous roles in adaptive immune responses. Importantly, Ca(2+) signaling is essential for T cell activation, tolerance of self-antigens, and homeostasis. Supporting the essential role of Ca(2+) signaling in T cell biology, the Ca(2+) regulated protein phosphatase calcineurin is a key target of pharmacologic inhibition for preventing allograft rejection and for autoimmune therapy. Recent studies have highlighted the unique role of Stim1 and Orai1/2 proteins in the regulation of store-operated/calcium release activated calcium (CRAC) channels in the context of T cells. While Ca(2+) is known to modulate T cell activation via effects on calcineurin and its target, nuclear factor of activated T cells (NFAT), this second messenger also regulates other pathways, including protein kinase C, calmodulin kinases, and cytoskeletal proteins. Ca(2+) also modulates the unique metabolic changes that occur during in distinct T cell stages and subsets. Herein, we discuss the means by which Ca(2+) mobilization modulates cellular metabolism following T cell receptor ligation. Further, we highlight the crosstalk between mitochondrial metabolism, reactive oxygen species (ROS) generation, and CRAC channel activity. As a target of mitochondrial ROS and Ca(2+) regulation, we describe the involvement of the serine/threonine kinase DRAK2 in the context of these processes. Given the important roles for Ca(2+) dependent signaling and cellular metabolism in adaptive immune responses, the crosstalk between these pathways is likely to be important for the regulation of T cell activation, tolerance, and homeostasis.

No MeSH data available.


Related in: MedlinePlus

Regulation of DRAK2 activity in T cells via Ca2+-induced respiratory burst. TCR induced Ca2+ depletion from ER stores results in opening of CRAC channels. This high cytosolic [Ca2+] promotes the induction of TCA cycle and OXPHOS in mitochondria, the latter of which release ROS as an OXPHOS byproduct. In addition to inhibiting phosphatases, ROS activate PKD, which itself binds to and activates DRAK2 (likely through transphosphorylation on DRAK2). DRAK2 then impacts Ca2+ signaling by altering SERCA activity (hypothetical), or other unknown substrates.
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Figure 3: Regulation of DRAK2 activity in T cells via Ca2+-induced respiratory burst. TCR induced Ca2+ depletion from ER stores results in opening of CRAC channels. This high cytosolic [Ca2+] promotes the induction of TCA cycle and OXPHOS in mitochondria, the latter of which release ROS as an OXPHOS byproduct. In addition to inhibiting phosphatases, ROS activate PKD, which itself binds to and activates DRAK2 (likely through transphosphorylation on DRAK2). DRAK2 then impacts Ca2+ signaling by altering SERCA activity (hypothetical), or other unknown substrates.

Mentions: Curiously, DRAK2 catalytic activity in activated T cells also depends on mitochondrial ROS, as antioxidants blocked Ser12 autophosphorylation (136). Since the electron transport complex III inhibitor FCCP led to Ser12 phosphorylation independent of antigenic stimulation of T cells, these findings demonstrate that ROS are both necessary and sufficient to promote DRAK2 catalytic activity. PKD activity is itself subject to activation by mitochondrial ROS (137, 138), and thus ROS induced by enhanced mitochondrial respiration that results from TCR stimulation likely participates in PKD-mediated DRAK2 activation (Figure 3). The specific nature of the interaction between mitochondrial ROS and DRAK2’s substrates is poorly understood. However, as DRAK2-deficient T cells bear enhanced CRAC activity (136), and DRAK2-transgenic thymocytes have diminished Ca2+ mobilization following TCR stimulation (132), it is likely that DRAK2 may phosphorylate an intermediate in CRAC signaling. DRAK2 has been shown to phosphorylate S6K1 (139), an important target of mTOR and of TCR signaling that impacts cellular metabolism (22, 57, 140). Thus, DRAK2 may itself serve as an important link between calcium and mTOR signaling, impacting the differentiation and survival of T cell subsets selectively required for immune responsiveness.


Modulation of T Cell Metabolism and Function through Calcium Signaling.

Fracchia KM, Pai CY, Walsh CM - Front Immunol (2013)

Regulation of DRAK2 activity in T cells via Ca2+-induced respiratory burst. TCR induced Ca2+ depletion from ER stores results in opening of CRAC channels. This high cytosolic [Ca2+] promotes the induction of TCA cycle and OXPHOS in mitochondria, the latter of which release ROS as an OXPHOS byproduct. In addition to inhibiting phosphatases, ROS activate PKD, which itself binds to and activates DRAK2 (likely through transphosphorylation on DRAK2). DRAK2 then impacts Ca2+ signaling by altering SERCA activity (hypothetical), or other unknown substrates.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3795426&req=5

Figure 3: Regulation of DRAK2 activity in T cells via Ca2+-induced respiratory burst. TCR induced Ca2+ depletion from ER stores results in opening of CRAC channels. This high cytosolic [Ca2+] promotes the induction of TCA cycle and OXPHOS in mitochondria, the latter of which release ROS as an OXPHOS byproduct. In addition to inhibiting phosphatases, ROS activate PKD, which itself binds to and activates DRAK2 (likely through transphosphorylation on DRAK2). DRAK2 then impacts Ca2+ signaling by altering SERCA activity (hypothetical), or other unknown substrates.
Mentions: Curiously, DRAK2 catalytic activity in activated T cells also depends on mitochondrial ROS, as antioxidants blocked Ser12 autophosphorylation (136). Since the electron transport complex III inhibitor FCCP led to Ser12 phosphorylation independent of antigenic stimulation of T cells, these findings demonstrate that ROS are both necessary and sufficient to promote DRAK2 catalytic activity. PKD activity is itself subject to activation by mitochondrial ROS (137, 138), and thus ROS induced by enhanced mitochondrial respiration that results from TCR stimulation likely participates in PKD-mediated DRAK2 activation (Figure 3). The specific nature of the interaction between mitochondrial ROS and DRAK2’s substrates is poorly understood. However, as DRAK2-deficient T cells bear enhanced CRAC activity (136), and DRAK2-transgenic thymocytes have diminished Ca2+ mobilization following TCR stimulation (132), it is likely that DRAK2 may phosphorylate an intermediate in CRAC signaling. DRAK2 has been shown to phosphorylate S6K1 (139), an important target of mTOR and of TCR signaling that impacts cellular metabolism (22, 57, 140). Thus, DRAK2 may itself serve as an important link between calcium and mTOR signaling, impacting the differentiation and survival of T cell subsets selectively required for immune responsiveness.

Bottom Line: While Ca(2+) is known to modulate T cell activation via effects on calcineurin and its target, nuclear factor of activated T cells (NFAT), this second messenger also regulates other pathways, including protein kinase C, calmodulin kinases, and cytoskeletal proteins.As a target of mitochondrial ROS and Ca(2+) regulation, we describe the involvement of the serine/threonine kinase DRAK2 in the context of these processes.Given the important roles for Ca(2+) dependent signaling and cellular metabolism in adaptive immune responses, the crosstalk between these pathways is likely to be important for the regulation of T cell activation, tolerance, and homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology and Biochemistry, The Institute for Immunology, University of California Irvine , Irvine, CA , USA.

ABSTRACT
As a vital second messenger in the activation of lymphocytes, the divalent cation Ca(2+) plays numerous roles in adaptive immune responses. Importantly, Ca(2+) signaling is essential for T cell activation, tolerance of self-antigens, and homeostasis. Supporting the essential role of Ca(2+) signaling in T cell biology, the Ca(2+) regulated protein phosphatase calcineurin is a key target of pharmacologic inhibition for preventing allograft rejection and for autoimmune therapy. Recent studies have highlighted the unique role of Stim1 and Orai1/2 proteins in the regulation of store-operated/calcium release activated calcium (CRAC) channels in the context of T cells. While Ca(2+) is known to modulate T cell activation via effects on calcineurin and its target, nuclear factor of activated T cells (NFAT), this second messenger also regulates other pathways, including protein kinase C, calmodulin kinases, and cytoskeletal proteins. Ca(2+) also modulates the unique metabolic changes that occur during in distinct T cell stages and subsets. Herein, we discuss the means by which Ca(2+) mobilization modulates cellular metabolism following T cell receptor ligation. Further, we highlight the crosstalk between mitochondrial metabolism, reactive oxygen species (ROS) generation, and CRAC channel activity. As a target of mitochondrial ROS and Ca(2+) regulation, we describe the involvement of the serine/threonine kinase DRAK2 in the context of these processes. Given the important roles for Ca(2+) dependent signaling and cellular metabolism in adaptive immune responses, the crosstalk between these pathways is likely to be important for the regulation of T cell activation, tolerance, and homeostasis.

No MeSH data available.


Related in: MedlinePlus