The Proapoptotic Factors Bax and Bak Regulate T Cell Proliferation through Control of Endoplasmic Reticulum Ca2+ Homeostasis

Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Immunity (Impact Factor: 21.56). 09/2007; 27(2):268-80. DOI: 10.1016/j.immuni.2007.05.023
Source: PubMed


The Bcl-2-associated X protein (Bax) and Bcl-2-antagonist/killer (Bak) are essential regulators of lymphocyte apoptosis, but whether they play a role in viable T cell function remains unclear. Here, we report that T cells lacking both Bax and Bak display defects in antigen-specific proliferation because of Ca(2+)-signaling defects. Bax(-/-), Bak(-/-) T cells displayed defective T cell receptor (TCR)- and inositol-1,4,5-trisphosphate (IP(3))-dependent Ca(2+) mobilization because of altered endoplasmic reticulum (ER) Ca(2+) regulation that was reversed by Bax's reintroduction. The ability of TCR-dependent Ca(2+) signals to stimulate mitochondrial NADH production in excess of that utilized for ATP synthesis was dependent on Bax and Bak. Blunting of Ca(2+)-induced mitochondrial NADH elevation in the absence of Bax and Bak resulted in decreased reactive-oxygen-species production, which was required for T cell proliferation. Together, the data establish that Bax and Bak play an essential role in the control of T cell proliferation by modulating ER Ca(2+) release.

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Available from: Martin D Bootman, Oct 02, 2015
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    • "Following release from the thymus, antigenic stimulation of mature T cells facilitates metabolic changes that support various bioenergetically dependent processes needed for rapid clonal expansion (9). It is proposed that T cells must shift from catabolic to anabolic metabolism in order to rapidly proliferate, likely allowing them to respond to microbial infection [(10) p. 2313]. Indeed, CD8 T cells have the capacity to divide once every 4–6 h (13), a process that is highly energy dependent. "
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    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.
    Frontiers in Immunology 10/2013; 4:324. DOI:10.3389/fimmu.2013.00324
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    • "For one, Bax has been shown to regulate the levels of ROS in healthy neurons (Kirkland and Franklin, 2007). Bax and Bak together also regulate ER calcium homeostasis in lymphocytes (Jones et al., 2007). In addition, Bax has been observed to form foci at mitochondrial fission sites in healthy cells (Karbowski et al., 2002), and deletion of Bax and Bak alters the normal rate of mitochondrial fusion (Karbowski et al., 2006). "
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    ABSTRACT: For single-cell organisms, nutrient uptake and metabolism are central to the fundamental decision of whether to grow or divide. In metazoans, cell fate decisions are more complex: organismal homeostasis must be strictly maintained by balancing cell proliferation and death. Despite this increased complexity, cell fate within multicellular organisms is also influenced by metabolism; recent studies, triggered in part by an interest in tumor metabolism, are beginning to illuminate the mechanisms through which proliferation, death, and metabolism are intertwined. In particular, work on Bcl-2 family proteins suggests that the signaling pathways governing metabolism and apoptosis are inextricably linked. Here we review the crosstalk between these pathways, emphasizing recent work that illustrates the emerging dual nature of several core apoptotic proteins in regulating both metabolism and cell death.
    Molecular cell 02/2013; 49(3):399-410. DOI:10.1016/j.molcel.2012.12.026 · 14.02 Impact Factor
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    • "l point for initiation of apoptosis in response to several stimuli , such as arachidonic acid , ceramide , and H 2 O 2 ( Scorrano et al . 2003 ) . Subsequent studies have shown , however , that ER calcium regulation is also involved in nonapoptotic functions of these proteins ( i . e . , mitochondrial energy me - tabolism and T - cell activation [ Jones et al . 2007 ] ) , suggesting that ER Ca 2þ regulation rep - resents another day - job function of these pro - teins . Such nonapoptotic functions of BCL - 2 proteins appear to be conserved as the zebrafish BCL - 2 homolog Nrz has been recently shown to control the cytoskeletal dynamics during ze - brafish development by regulating ER Ca 2þ re - lea"
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    ABSTRACT: BCL-2 family proteins are the regulators of apoptosis, but also have other functions. This family of interacting partners includes inhibitors and inducers of cell death. Together they regulate and mediate the process by which mitochondria contribute to cell death known as the intrinsic apoptosis pathway. This pathway is required for normal embryonic development and for preventing cancer. However, before apoptosis is induced, BCL-2 proteins have critical roles in normal cell physiology related to neuronal activity, autophagy, calcium handling, mitochondrial dynamics and energetics, and other processes of normal healthy cells. The relative importance of these physiological functions compared to their apoptosis functions in overall organismal physiology is difficult to decipher. Apoptotic and noncanonical functions of these proteins may be intertwined to link cell growth to cell death. Disentanglement of these functions may require delineation of biochemical activities inherent to the characteristic three-dimensional shape shared by distantly related viral and cellular BCL-2 family members.
    Cold Spring Harbor perspectives in biology 02/2013; 5(2). DOI:10.1101/cshperspect.a008722 · 8.68 Impact Factor
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