- Email: [email protected]
Mitochondria-ER Pas de Deux Controls Memory T Cell Function
Immunity
Previews Mitochondria-ER Pas de Deux Controls Memory T Cell Function Elizabeth M. Steinert1 and Navdeep S. Chandel1,* 1Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA *Correspondence: [email protected] https://doi.org/10.1016/j.immuni.2018.03.002
Memory CD8+ T cells mediate protective secondary immune responses. In this issue, Bantug et al. (2018) demonstrate that mTORC2-AKT-GSK3b signaling at mitochondria-ER contact sites enables the TCA cycle flux that is necessary for memory CD8+ T cells to produce IFN-g. Upon activation, CD8+ T cells proliferate and differentiate, generating a large population of responders with potent functions to combat the activating pathogen. After the primary infection resolves, some responders will die but those that remain become memory CD8+ T cells, which can rapidly exert protective effector functions upon secondary activation. Because of their longevity, potency, and access to non-lymphoid tissues, the intracellular mechanisms regulating memory CD8+ T cell phenotype and function have long been of interest. In the last several years, a renaissance of metabolism research has revealed that distinct phenotypic and activation states of CD8+ T cells are in part regulated by metabolic changes. In this issue of Immunity, Bantug et al. (2018) identify the physical subcellular reorganization of mitochondria-endoplasmic reticulum (ER) contact sites which mediate the mTORC2-AKT-GSK3b signaling cascade to promote hexokinase binding to VDAC, resulting in an increase in pyruvate oxidation by the mitochondrial tricarboxylic acid (TCA) cycle, which is necessary for rapid interferon-g (IFN-g) production by memory CD8+ T cells. Mitochondria are classically recognized as bioenergetic and biosynthetic organelles, charged with generating ATP and metabolites for macromolecule (e.g., lipids and nucleotides) synthesis. Previous work has largely focused on the bioenergetic and biosynthetic functions of mitochondria as providing the necessities of memory CD8+ T cell function (Klein Geltink et al., 2017). Additionally, dynamic fission or fusion states of mitochondria have been noted to correspond with mitochondrial metabolic activity and implicated in regulating CD8+ T cell function (Buck et al., 2016). However, it is
becoming increasingly appreciated that mitochondria also function as signaling organelles by releasing reactive oxygen species and metabolites that can alter transcription factors and epigenetics, respectively, thus orchestrating innate and adaptive immunity (Mehta et al., 2017). Mitochondria can also interact with other organelles, such as the endoplasmic reticulum (ER). These contact sites can serve as signaling hubs within the cell (Murley and Nunnari, 2016). How the dynamic changes of mitochondria form relate to their function as signaling organelles to control CD8+ memory T cell function has not been well established. Bantug et al. (2018) examine the intracellular re-organization of mitochondria within memory CD8+ T cells to determine how IFN-g is rapidly produced upon secondary stimulation. They observed an abundance of mitochondria-ER contact sites in effector memory (EM) CD8+ T cells compared to naive CD8+ T cells. The addition of nocodazole, a microtubule polymerization inhibitor, disrupted mitochondria-ER contact sites and abrogated activation-induced increases in mitochondrial respiration in memory CD8+ T cells. Bantug et al. (2018) deciphered the molecular interactions occurring in the abundant mitochondria-ER contact sites using a fractionation protocol to separate pure mitochondria (PM), mitochondria-ER junctions (MEJ), and ER, Golgi, and cytoplasm (EGC). Using this method, they found that mTORC2 complex and the kinase AKT are localized to mitochondria-ER junctions of memory CD8+ T cells. Phosphorylated AKT at MEJs was reduced in memory CD8+ T cells deficient in Rictor (a component of the mTORC2 complex), indicating that
localization of mTORC2 and AKT at mitochondria-ER junctions facilitates phosphorylation of AKT. Indeed, nocodazolemediated dissociation of MEJs resulted in decreased AKT phosphorylation. Further, when either mTORC2 or AKT were inhibited, the activation-induced increase in mitochondrial respiration typically observed in memory CD8+ T cells was diminished. Moreover, the loss of Rictor diminished rapid recall of memory CD8+ T cells in vitro and in vivo, highlighting the essential function of mTORC2-AKT signaling in controlling memory CD8+ T cells. One challenge for the field of mitochondria-ER contact sites is that there is no consensus on what proteins tether these two organelles (Murley and Nunnari, 2016). Thus, presently it is challenging to causally link mitochondria-ER contact sites to cellular function. Going forward, deciphering the proteins that are exclusive tethers for mitochondria-ER interaction will be imperative to decipher the biological relevance of these contact sites. Treatments such as microtubule depolymerization with nocadozole are likely to disrupt many processes beyond contact sites. Nevertheless, the authors found that phosphorylated (and thus, inhibited) GSK3b was enriched in MEJ fractions. This enrichment was dependent on mTORC2 phosphorylation of AKT. Previous findings suggested that GSK3b inactivation would permit hexokinase binding to the voltage-dependent anion channel (VDAC). Accordingly, the authors identify increased hexokinase I in MEJ fractions from activated CD8+ T cells compared to inactivated counterparts. Hexokinases catalyze the first step in glycolysis, converting glucose to glucose-6-phosphate, and have been previously shown to bind
Immunity 47, March 20, 2018 ª 2018 Elsevier Inc. 479
Immunity
Previews
Figure 1. Mitochondria-ER Contact Sites Facilitate the Metabolic Changes Necessary for Memory T Cell Function During differentiation, memory CD8+ T cells reorganize subcellular compartments to increase abundance of mitochondria-endoplasmic reticulum (ER) contact sites. These mitochondria-ER contact sites facilitate mTORC2-mediated phosphorylation of AKT, which in turn phosphorylates (thus inhibiting) GSK3b. Inactivated GSK3b can no longer prevent hexokinase1 (HK1) from docking with VDAC, thus enabling transfer of cytosolic metabolites including pyruvate into the mitochondria. Pyruvate flux into the mitochondria results in TCA cycle production of citrate. Citrate exported into the cytosol can then be converted by ATP citrate lyase (ACYL) into acetyl-CoA (Ac) and oxaloacetate (OAA), which provides the Ac necessary for acetylation, thus increasing transcription and production of IFN-g.
VDAC in an AKT-dependent manner (Majewski et al., 2004). Thus, the authors formulated a stepwise molecular structure specific to memory CD8+ T cells which, through tethering mitochondria to ER, provides stable availability of actors in the mTORC-AKT-GSK3b signaling pathway, which facilitates recruitment of hexokinase to VDAC at the mitochondria membrane. Hexokinase binding to VDAC increased transfer of cytoplasmic metabolites to support mitochondrial respiration. Importantly, pharmacological inhibition of hexokinase binding to VDAC in recently re-activated memory CD8+ T cells markedly diminished mitochondrial respiration, but not aerobic glycolysis. Next, Bantug et al. (2018) used carbonlabeled glucose to test whether the in480 Immunity 47, March 20, 2018
crease in mitochondrial respiration is accompanied with enhanced TCA cycle flux. Glucose metabolism through glycolysis generates pyruvate that is either converted to lactate in the cytosol by lactate dehyrogenase (LDH) or enters the mitochondrial TCA cycle where it is oxidized to acetyl-CoA by pyruvate dehydrogenase (PDH). Indeed, glucose-derived lactate but also TCA cycle intermediates citrate, malate, and aspartate were significantly increased following activation of CD8+ T cells, in an AKT-dependent manner. Pharmacologic inhibition of PDH but not LDH decreased IFN-g production suggesting that oxidation of glucose carbons in the mitochondria is necessary for secondary effector functions. Interestingly, treatment with 2-de-
oxyglucose, which prevents hexokinasedependent glucose metabolism through glycolysis, also decreased IFN-g production, which was fully restored in the presence of methyl-pyruvate. Collectively, these experiments demonstrate that glucose is necessary to generate pyruvate for oxidation by the TCA cycle to enable downstream IFN-g production. The TCA cycle converts NAD and FAD to NADH and FADH2, respectively, resulting in the generation of metabolites. NADH and FADH2 are regenerated to NAD and FAD by donating electrons to the respiratory chain, which generates a proton-motive force to produce ATP (i.e., oxidative phosphorylation). To test whether the necessity of the TCA cycle for IFN-g production is due to TCA cycle metabolites or ATP generation, the authors treated CD8+ T cells with the uncoupler FCCP, which dissipates the protonmotive force abolishing ATP production. However, FCCP does permit for the regeneration of NAD and FAD which allows the TCA cycle to generate metabolites. FCCP did not affect IFN-g production. However, blocking pyruvate entry into the mitochondria in the presence of FCCP diminished IFN-g production. These simple yet informative experiments suggest that pyruvate-dependent generation of TCA cycle metabolites, but not ATP production, is necessary for IFN-g production. It will be important to genetically validate the requirement of pyruvate entry into the mitochondria by using mice conditionally deficient for the mitochondrial pyruvate carrier proteins 1 or 2. How might TCA cycle metabolites be linked to IFN-g production? Previous studies have indicated that TCA cycle metabolites are essential for histone acetylation (Martı´nez-Reyes et al., 2016). The TCA cycle generates citrate which is exported into the cytosol where ATP citrate lyase (ACLY) converts citrate into acetylCoA, the substrate for histone acetylation (Su et al., 2016). The authors have previously demonstrated that acetylation of H3K9 at the IFNG promoter is dependent on glycolysis (Gubser et al., 2013). Thus, they surmised that glycolytic generation of pyruvate, which produces acetyl-CoA and ultimately citrate in the TCA cycle, was necessary for histone acetylation and IFN-g production. Indeed, addition of an ATP citrate lyase inhibitor, which decreases acetyl-CoA pools in the cytosol,
Immunity
Previews reduced IFN-g production. A similar effect was observed upon inhibition of histone acetyltransferase. These studies are conceptually consistent with previous results demonstrating that decreasing citrate-derived acetyl-CoA diminishes histone acetylation and IFNG mRNA transcription in T helper 1 effector CD4+ T cells (Peng et al., 2016). Collectively, these experiments suggest that the major function of glycolysis in memory CD8+ T cells is to provide carbons to generate citrate in the mitochondria and ultimately drive the histone acetylation necessary for IFN-g production. In summary, Bantug et al. (2018) link intracellular signal transduction pathways (i.e., mTORC2-AKT-GSK3b) to the TCA cycle metabolite citrate and epigenetic changes for IFN-g production, through hexokinase binding to VDAC (Figure 1). Collectively, their work highlights the intersection of mitochondrial form and intracellular organization, with the function of enabling signaling transduction and mitochondrial
metabolism to result in epigenetic changes controlling rapid effector functions. This is an exciting finding that reinforces mitochondrial signaling, an emerging dominant theme in immunity. REFERENCES €hlert, J., Balmer, M.L., Bantug, G.R., Fischer, M., Gra Unterstab, G., Develioglu, L., Steiner, R., Zhang, L., Costa, A.S.H., Gubser, P.M., et al. (2018). Mitochondria-endoplasmic reticulum contact sites function as immunometabolic hubs that orchestrate the rapid recall response of memory CD8+ T cells. Immunity 48, this issue, 542–555. Buck, M.D., O’Sullivan, D., Klein Geltink, R.I., Curtis, J.D., Chang, C.-H., Sanin, D.E., Qiu, J., Kretz, O., Braas, D., van der Windt, G.J.W., et al. (2016). Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 166, 63–76.
(2017). Mitochondrial priming by CD28. Cell 171, 385–397.e11. Majewski, N., Nogueira, V., Bhaskar, P., Coy, P.E., Skeen, J.E., Gottlob, K., Chandel, N.S., Thompson, C.B., Robey, R.B., and Hay, N. (2004). Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol. Cell 16, 819–830. Martı´nez-Reyes, I., Diebold, L.P., Kong, H., Schieber, M., Huang, H., Hensley, C.T., Mehta, M.M., Wang, T., Santos, J.H., Woychik, R., et al. (2016). TCA cycle and mitochondrial membrane potential are necessary for diverse biological functions. Mol. Cell 61, 199–209. Mehta, M.M., Weinberg, S.E., and Chandel, N.S. (2017). Mitochondrial control of immunity: beyond ATP. Nat. Rev. Immunol. 17, 608–620. Murley, A., and Nunnari, J. (2016). The emerging network of mitochondria-organelle contacts. Mol. Cell 61, 648–653.
Gubser, P.M., Bantug, G.R., Razik, L., Fischer, M., Dimeloe, S., Hoenger, G., Durovic, B., Jauch, A., and Hess, C. (2013). Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch. Nat. Immunol. 14, 1064–1072.
Peng, M., Yin, N., Chhangawala, S., Xu, K., Leslie, C.S., and Li, M.O. (2016). Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354, 481–484.
Klein Geltink, R.I., O’Sullivan, D., Corrado, M., Bremser, A., Buck, M.D., Buescher, J.M., Firat, E., Zhu, X., Niedermann, G., Caputa, G., et al.
Su, X., Wellen, K.E., and Rabinowitz, J.D. (2016). Metabolic control of methylation and acetylation. Curr. Opin. Chem. Biol. 30, 52–60.
Sterile Inflammation Fuels Gastric Cancer Antonella Montinaro1 and Henning Walczak1,* 1Centre for Cell Death, Cancer and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK *Correspondence: [email protected] https://doi.org/10.1016/j.immuni.2018.03.011
Constitutively activated NF-kB signaling has long been known to be oncogenic. In this issue of Immunity, O’Reilly et al. (2018) unveil a link between loss of NF-kB1, aberrant STAT1 signaling, sterile inflammation, and the increased expression of immune checkpoint molecules as cancer drivers. The family of transcription factors referred to as nuclear factor kappa B (NF-kB) regulates the transcription of many genes involved in central physiological processes. These include, among others, cell proliferation, differentiation, survival, and death as well as inflammation and the overall orchestration of the immune response. In addition, dysregulated NF-kB signaling has long been known to exert functions in autoimmunity (Sun et al., 2013) and tumorigenesis, particularly the development of inflammationassociated cancers, such as chemical
injury-induced development of liver cancer (Karin, 2009). However, the precise role of the various members of the NF-kB family in tumorigenesis is largely unknown. In this issue of Immunity, O’Reilly et al. (2018) elegantly demonstrate a role for NF-kB1 in tumor suppression. The family of protein dimers referred to as NF-kB are formed by the combination of members of the so-called reticuloendotheliosis (Rel) protein family. The members of this family are characterized by a Rel homology domain, which confers the ability to dimerize and to bind DNA. Based
on structure, function, and biosynthesis, the REL protein family can be classified into two distinct groups. The first group is comprised of RelA (also known as p65), RelB, and cRel, which have intrinsic transcriptional transactivation function and do not require proteolytic processing, as they are synthesized in the mature form. The second group consists of NF-kB1 (also known as p105) and NF-kB2 (also known as p100), which lack intrinsic transcriptional transactivation function and require proteolytic processing to generate the mature p50 and
Immunity 47, March 20, 2018 ª 2018 Elsevier Inc. 481
Previews Mitochondria-ER Pas de Deux Controls Memory T Cell Function Elizabeth M. Steinert1 and Navdeep S. Chandel1,* 1Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA *Correspondence: [email protected] https://doi.org/10.1016/j.immuni.2018.03.002
Memory CD8+ T cells mediate protective secondary immune responses. In this issue, Bantug et al. (2018) demonstrate that mTORC2-AKT-GSK3b signaling at mitochondria-ER contact sites enables the TCA cycle flux that is necessary for memory CD8+ T cells to produce IFN-g. Upon activation, CD8+ T cells proliferate and differentiate, generating a large population of responders with potent functions to combat the activating pathogen. After the primary infection resolves, some responders will die but those that remain become memory CD8+ T cells, which can rapidly exert protective effector functions upon secondary activation. Because of their longevity, potency, and access to non-lymphoid tissues, the intracellular mechanisms regulating memory CD8+ T cell phenotype and function have long been of interest. In the last several years, a renaissance of metabolism research has revealed that distinct phenotypic and activation states of CD8+ T cells are in part regulated by metabolic changes. In this issue of Immunity, Bantug et al. (2018) identify the physical subcellular reorganization of mitochondria-endoplasmic reticulum (ER) contact sites which mediate the mTORC2-AKT-GSK3b signaling cascade to promote hexokinase binding to VDAC, resulting in an increase in pyruvate oxidation by the mitochondrial tricarboxylic acid (TCA) cycle, which is necessary for rapid interferon-g (IFN-g) production by memory CD8+ T cells. Mitochondria are classically recognized as bioenergetic and biosynthetic organelles, charged with generating ATP and metabolites for macromolecule (e.g., lipids and nucleotides) synthesis. Previous work has largely focused on the bioenergetic and biosynthetic functions of mitochondria as providing the necessities of memory CD8+ T cell function (Klein Geltink et al., 2017). Additionally, dynamic fission or fusion states of mitochondria have been noted to correspond with mitochondrial metabolic activity and implicated in regulating CD8+ T cell function (Buck et al., 2016). However, it is
becoming increasingly appreciated that mitochondria also function as signaling organelles by releasing reactive oxygen species and metabolites that can alter transcription factors and epigenetics, respectively, thus orchestrating innate and adaptive immunity (Mehta et al., 2017). Mitochondria can also interact with other organelles, such as the endoplasmic reticulum (ER). These contact sites can serve as signaling hubs within the cell (Murley and Nunnari, 2016). How the dynamic changes of mitochondria form relate to their function as signaling organelles to control CD8+ memory T cell function has not been well established. Bantug et al. (2018) examine the intracellular re-organization of mitochondria within memory CD8+ T cells to determine how IFN-g is rapidly produced upon secondary stimulation. They observed an abundance of mitochondria-ER contact sites in effector memory (EM) CD8+ T cells compared to naive CD8+ T cells. The addition of nocodazole, a microtubule polymerization inhibitor, disrupted mitochondria-ER contact sites and abrogated activation-induced increases in mitochondrial respiration in memory CD8+ T cells. Bantug et al. (2018) deciphered the molecular interactions occurring in the abundant mitochondria-ER contact sites using a fractionation protocol to separate pure mitochondria (PM), mitochondria-ER junctions (MEJ), and ER, Golgi, and cytoplasm (EGC). Using this method, they found that mTORC2 complex and the kinase AKT are localized to mitochondria-ER junctions of memory CD8+ T cells. Phosphorylated AKT at MEJs was reduced in memory CD8+ T cells deficient in Rictor (a component of the mTORC2 complex), indicating that
localization of mTORC2 and AKT at mitochondria-ER junctions facilitates phosphorylation of AKT. Indeed, nocodazolemediated dissociation of MEJs resulted in decreased AKT phosphorylation. Further, when either mTORC2 or AKT were inhibited, the activation-induced increase in mitochondrial respiration typically observed in memory CD8+ T cells was diminished. Moreover, the loss of Rictor diminished rapid recall of memory CD8+ T cells in vitro and in vivo, highlighting the essential function of mTORC2-AKT signaling in controlling memory CD8+ T cells. One challenge for the field of mitochondria-ER contact sites is that there is no consensus on what proteins tether these two organelles (Murley and Nunnari, 2016). Thus, presently it is challenging to causally link mitochondria-ER contact sites to cellular function. Going forward, deciphering the proteins that are exclusive tethers for mitochondria-ER interaction will be imperative to decipher the biological relevance of these contact sites. Treatments such as microtubule depolymerization with nocadozole are likely to disrupt many processes beyond contact sites. Nevertheless, the authors found that phosphorylated (and thus, inhibited) GSK3b was enriched in MEJ fractions. This enrichment was dependent on mTORC2 phosphorylation of AKT. Previous findings suggested that GSK3b inactivation would permit hexokinase binding to the voltage-dependent anion channel (VDAC). Accordingly, the authors identify increased hexokinase I in MEJ fractions from activated CD8+ T cells compared to inactivated counterparts. Hexokinases catalyze the first step in glycolysis, converting glucose to glucose-6-phosphate, and have been previously shown to bind
Immunity 47, March 20, 2018 ª 2018 Elsevier Inc. 479
Immunity
Previews
Figure 1. Mitochondria-ER Contact Sites Facilitate the Metabolic Changes Necessary for Memory T Cell Function During differentiation, memory CD8+ T cells reorganize subcellular compartments to increase abundance of mitochondria-endoplasmic reticulum (ER) contact sites. These mitochondria-ER contact sites facilitate mTORC2-mediated phosphorylation of AKT, which in turn phosphorylates (thus inhibiting) GSK3b. Inactivated GSK3b can no longer prevent hexokinase1 (HK1) from docking with VDAC, thus enabling transfer of cytosolic metabolites including pyruvate into the mitochondria. Pyruvate flux into the mitochondria results in TCA cycle production of citrate. Citrate exported into the cytosol can then be converted by ATP citrate lyase (ACYL) into acetyl-CoA (Ac) and oxaloacetate (OAA), which provides the Ac necessary for acetylation, thus increasing transcription and production of IFN-g.
VDAC in an AKT-dependent manner (Majewski et al., 2004). Thus, the authors formulated a stepwise molecular structure specific to memory CD8+ T cells which, through tethering mitochondria to ER, provides stable availability of actors in the mTORC-AKT-GSK3b signaling pathway, which facilitates recruitment of hexokinase to VDAC at the mitochondria membrane. Hexokinase binding to VDAC increased transfer of cytoplasmic metabolites to support mitochondrial respiration. Importantly, pharmacological inhibition of hexokinase binding to VDAC in recently re-activated memory CD8+ T cells markedly diminished mitochondrial respiration, but not aerobic glycolysis. Next, Bantug et al. (2018) used carbonlabeled glucose to test whether the in480 Immunity 47, March 20, 2018
crease in mitochondrial respiration is accompanied with enhanced TCA cycle flux. Glucose metabolism through glycolysis generates pyruvate that is either converted to lactate in the cytosol by lactate dehyrogenase (LDH) or enters the mitochondrial TCA cycle where it is oxidized to acetyl-CoA by pyruvate dehydrogenase (PDH). Indeed, glucose-derived lactate but also TCA cycle intermediates citrate, malate, and aspartate were significantly increased following activation of CD8+ T cells, in an AKT-dependent manner. Pharmacologic inhibition of PDH but not LDH decreased IFN-g production suggesting that oxidation of glucose carbons in the mitochondria is necessary for secondary effector functions. Interestingly, treatment with 2-de-
oxyglucose, which prevents hexokinasedependent glucose metabolism through glycolysis, also decreased IFN-g production, which was fully restored in the presence of methyl-pyruvate. Collectively, these experiments demonstrate that glucose is necessary to generate pyruvate for oxidation by the TCA cycle to enable downstream IFN-g production. The TCA cycle converts NAD and FAD to NADH and FADH2, respectively, resulting in the generation of metabolites. NADH and FADH2 are regenerated to NAD and FAD by donating electrons to the respiratory chain, which generates a proton-motive force to produce ATP (i.e., oxidative phosphorylation). To test whether the necessity of the TCA cycle for IFN-g production is due to TCA cycle metabolites or ATP generation, the authors treated CD8+ T cells with the uncoupler FCCP, which dissipates the protonmotive force abolishing ATP production. However, FCCP does permit for the regeneration of NAD and FAD which allows the TCA cycle to generate metabolites. FCCP did not affect IFN-g production. However, blocking pyruvate entry into the mitochondria in the presence of FCCP diminished IFN-g production. These simple yet informative experiments suggest that pyruvate-dependent generation of TCA cycle metabolites, but not ATP production, is necessary for IFN-g production. It will be important to genetically validate the requirement of pyruvate entry into the mitochondria by using mice conditionally deficient for the mitochondrial pyruvate carrier proteins 1 or 2. How might TCA cycle metabolites be linked to IFN-g production? Previous studies have indicated that TCA cycle metabolites are essential for histone acetylation (Martı´nez-Reyes et al., 2016). The TCA cycle generates citrate which is exported into the cytosol where ATP citrate lyase (ACLY) converts citrate into acetylCoA, the substrate for histone acetylation (Su et al., 2016). The authors have previously demonstrated that acetylation of H3K9 at the IFNG promoter is dependent on glycolysis (Gubser et al., 2013). Thus, they surmised that glycolytic generation of pyruvate, which produces acetyl-CoA and ultimately citrate in the TCA cycle, was necessary for histone acetylation and IFN-g production. Indeed, addition of an ATP citrate lyase inhibitor, which decreases acetyl-CoA pools in the cytosol,
Immunity
Previews reduced IFN-g production. A similar effect was observed upon inhibition of histone acetyltransferase. These studies are conceptually consistent with previous results demonstrating that decreasing citrate-derived acetyl-CoA diminishes histone acetylation and IFNG mRNA transcription in T helper 1 effector CD4+ T cells (Peng et al., 2016). Collectively, these experiments suggest that the major function of glycolysis in memory CD8+ T cells is to provide carbons to generate citrate in the mitochondria and ultimately drive the histone acetylation necessary for IFN-g production. In summary, Bantug et al. (2018) link intracellular signal transduction pathways (i.e., mTORC2-AKT-GSK3b) to the TCA cycle metabolite citrate and epigenetic changes for IFN-g production, through hexokinase binding to VDAC (Figure 1). Collectively, their work highlights the intersection of mitochondrial form and intracellular organization, with the function of enabling signaling transduction and mitochondrial
metabolism to result in epigenetic changes controlling rapid effector functions. This is an exciting finding that reinforces mitochondrial signaling, an emerging dominant theme in immunity. REFERENCES €hlert, J., Balmer, M.L., Bantug, G.R., Fischer, M., Gra Unterstab, G., Develioglu, L., Steiner, R., Zhang, L., Costa, A.S.H., Gubser, P.M., et al. (2018). Mitochondria-endoplasmic reticulum contact sites function as immunometabolic hubs that orchestrate the rapid recall response of memory CD8+ T cells. Immunity 48, this issue, 542–555. Buck, M.D., O’Sullivan, D., Klein Geltink, R.I., Curtis, J.D., Chang, C.-H., Sanin, D.E., Qiu, J., Kretz, O., Braas, D., van der Windt, G.J.W., et al. (2016). Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 166, 63–76.
(2017). Mitochondrial priming by CD28. Cell 171, 385–397.e11. Majewski, N., Nogueira, V., Bhaskar, P., Coy, P.E., Skeen, J.E., Gottlob, K., Chandel, N.S., Thompson, C.B., Robey, R.B., and Hay, N. (2004). Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol. Cell 16, 819–830. Martı´nez-Reyes, I., Diebold, L.P., Kong, H., Schieber, M., Huang, H., Hensley, C.T., Mehta, M.M., Wang, T., Santos, J.H., Woychik, R., et al. (2016). TCA cycle and mitochondrial membrane potential are necessary for diverse biological functions. Mol. Cell 61, 199–209. Mehta, M.M., Weinberg, S.E., and Chandel, N.S. (2017). Mitochondrial control of immunity: beyond ATP. Nat. Rev. Immunol. 17, 608–620. Murley, A., and Nunnari, J. (2016). The emerging network of mitochondria-organelle contacts. Mol. Cell 61, 648–653.
Gubser, P.M., Bantug, G.R., Razik, L., Fischer, M., Dimeloe, S., Hoenger, G., Durovic, B., Jauch, A., and Hess, C. (2013). Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch. Nat. Immunol. 14, 1064–1072.
Peng, M., Yin, N., Chhangawala, S., Xu, K., Leslie, C.S., and Li, M.O. (2016). Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354, 481–484.
Klein Geltink, R.I., O’Sullivan, D., Corrado, M., Bremser, A., Buck, M.D., Buescher, J.M., Firat, E., Zhu, X., Niedermann, G., Caputa, G., et al.
Su, X., Wellen, K.E., and Rabinowitz, J.D. (2016). Metabolic control of methylation and acetylation. Curr. Opin. Chem. Biol. 30, 52–60.
Sterile Inflammation Fuels Gastric Cancer Antonella Montinaro1 and Henning Walczak1,* 1Centre for Cell Death, Cancer and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK *Correspondence: [email protected] https://doi.org/10.1016/j.immuni.2018.03.011
Constitutively activated NF-kB signaling has long been known to be oncogenic. In this issue of Immunity, O’Reilly et al. (2018) unveil a link between loss of NF-kB1, aberrant STAT1 signaling, sterile inflammation, and the increased expression of immune checkpoint molecules as cancer drivers. The family of transcription factors referred to as nuclear factor kappa B (NF-kB) regulates the transcription of many genes involved in central physiological processes. These include, among others, cell proliferation, differentiation, survival, and death as well as inflammation and the overall orchestration of the immune response. In addition, dysregulated NF-kB signaling has long been known to exert functions in autoimmunity (Sun et al., 2013) and tumorigenesis, particularly the development of inflammationassociated cancers, such as chemical
injury-induced development of liver cancer (Karin, 2009). However, the precise role of the various members of the NF-kB family in tumorigenesis is largely unknown. In this issue of Immunity, O’Reilly et al. (2018) elegantly demonstrate a role for NF-kB1 in tumor suppression. The family of protein dimers referred to as NF-kB are formed by the combination of members of the so-called reticuloendotheliosis (Rel) protein family. The members of this family are characterized by a Rel homology domain, which confers the ability to dimerize and to bind DNA. Based
on structure, function, and biosynthesis, the REL protein family can be classified into two distinct groups. The first group is comprised of RelA (also known as p65), RelB, and cRel, which have intrinsic transcriptional transactivation function and do not require proteolytic processing, as they are synthesized in the mature form. The second group consists of NF-kB1 (also known as p105) and NF-kB2 (also known as p100), which lack intrinsic transcriptional transactivation function and require proteolytic processing to generate the mature p50 and
Immunity 47, March 20, 2018 ª 2018 Elsevier Inc. 481