- Email: [email protected]
Fifty Shades of α-Ketoglutarate on Cellular Programming
Molecular Cell
Previews Fifty Shades of a-Ketoglutarate on Cellular Programming Giusy Di Conza,1,2,3 Chin-Hsien Tsai,1,2,3 and Ping-Chih Ho1,2,* 1Department
of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland Institute for Cancer Research, University of Lausanne, E´palinges, Switzerland 3These authors contributed equally *Correspondence: [email protected] https://doi.org/10.1016/j.molcel.2019.09.002 2Ludwig
High plasticity to utilize different nutrients to adapt metabolic stress is one of the hallmarks for cancer cells. However, the underlying mechanisms by which cancer cells reprogram metabolic machinery in response to metabolic stress remain largely unclear. In this issue of Molecular Cell, Wang et al. (2019) report that glutamate dehydrogenase 1 (GDH1) induces an unconventional regulation of the NF-kB pathway under glucose deprivation, thereby stimulating glycolysis in glioblastomas. Gliomas are extremely aggressive tumors relying on aerobic glycolysis in response to hypoxia. In addition to glucose, glutamine metabolism plays a crucial role to ensure the survival of glioma cells when they experience glucose deprivation (Oizel et al., 2017). Activation of mitochondrial glutamate dehydrogenase 1 (GDH1) stimulates the conversion of glutaminederived glutamate into a-ketoglutarate (a-KG) for supporting energy production. a-KG can be further used for replenishing citrate, an anaplerotic reaction for the tricarboxylic acid (TCA) cycle in highly proliferating cells (Li et al., 2019). In addition, the production of a-KG can impact cellular behaviors by modulating activities of several dioxygenases, such as prolylhydroxylases and DNA demethylases, involved in hypoxic responses and epigenetic reprogramming (Cluntun et al., 2017). While it is clear how the production of a-KG can influence TCA cycle and signaling pathways, it remains unclear whether the generation of a-KG is involved in reprogramming metabolic machineries in cancer cells in response to glucose deprivation. In a study published in this issue of Molecular Cell, Wang et al. showed that activity of GDH1 in low-glucose conditions is needed to promote survival of glioma cells in an a-KG-dependent manner (Wang et al., 2019). In their search of the roles of GDH1 on supporting survival of glioma cells, the authors found that GDH1-depleted cells markedly reduced proliferation under glucose-deprived conditions. In contrast to utilizing gluta-
mine as an alternative nutrient in response to glucose deprivation, GDH1 deficiency led to marked downregulation of glycolytic intermediates and attenuated GLUT1 expression, suggesting that GDH1 may support glycolytic activity of glioma cells in a glucose-deprived condition. By exploiting mass spectrometry (MS) analysis, they further identified that glucose deprivation facilitated the formation of a protein complex containing GDH1, RelA, and the IkB kinase (IKK) complex. When knocking down GDH1 in glioma cells, the authors could suppress NF-kB-driven transcription activity and expression of GLUT1 and impair RelA binding on the promoter region of the GLUT1 gene. Given that NF-kB activation requires degradation of its direct inhibitor IkBa via IKKb-mediated phosphorylation on IkBa, the authors wondered whether the enzymatic activity of GDH1 is needed to activate IKKb and found that GDH1-generated a-KG can directly bind IKKb at residue R140. Intriguingly, binding of a-KG to IKKb stimulated IKKb kinase activity without engaging the conventional IKKb activation process, which relies on phosphorylation of serine 177 and serine 181 residues of IKKb. In addition, overexpressing a mutant form of IKKb (IKKb-R140L), which is unable to bind a-KG, in glioma cells attenuated tumor growth and prevented glucose-deprivation-induced activation of NF-kB and expression of GLUT1 (Figure 1). To further elucidate the underlying mechanism governing the GDH1-RelA
interaction upon glucose deprivation, the authors identified that phosphorylation at serine 384 of GDH1 is indispensable for the GDH1-RelA interaction and NF-kB activation under glucose deprivation. The authors then demonstrated that glucose-starvation-induced activation of AMP-dependent protein kinase (AMPK) causes the phosphorylation of the cytosolic form of GDH1 at serine 384. Importantly, mitochondrial GDH1 could not be phosphorylated by AMPK. These findings highlight a novel role of GDH1 in reprogramming cancer metabolisms that is distinguished from its classical role in the mitochondria. Notably, overexpression of the phosphor-deficient mutant form of GDH1 (GDH1 S384A) drastically attenuated glioma growth in a GLUT1dependent manner in the in vivo murine models. Wang et al. also evaluated the clinical relevance of these findings and demonstrated that the status of serine 384 phosphorylation on GDH1 was positively associated with malignancy grade and poor prognosis in human glioblastoma multiform patients. Together, these results uncover GDH1 pS384 as an independent predictor of prognosis in glioblastoma patients. Pediatric and adult glioblastoma are aggressive and incurable diseases, causing a high percentage of cancer mortality. Current therapy includes surgical resection followed by radiotherapy in combination with adjuvant chemotherapy, but the overall survival of these patients is very poor. Given the dependence of cancer cells on glutamine metabolism,
Molecular Cell 76, October 3, 2019 ª 2019 Elsevier Inc. 1
Molecular Cell
Previews
Figure 1. GDH-Mediated a-Ketoglutarate Production Elicits Compensatory Glycolysis in Response to Glucose Deprivation
Once entering cells, glutamine can be converted to a-KG through glutaminolysis mediated by GLS and GDH. a-KG either enters the TCA cycle to produce energy for cell growth or contributes to the metabolic recycling of ammonia for biomass production. Moreover, a-KG is a substrate of dioxygenase enzymes in the regulation of histone and DNA methylation or PHD-dependent IKK post-translational modification. In addition to that, in low-glucose conditions, cytosolic GDHderived a-KG can bind and activate IKKb, promoting NF-kB activation, Glut1 expression, and glycolysis. This regulation of IKKb is distinct from phosphorylationmediated activation and requires the interaction of phosphorylated GDH at serine 384.
targeted therapies have already been developed against glutamine metabolism, from glutamine uptake to glutamine-catalyzed enzymes. Inhibition of glutaminase (GLS) with CB-839 has been shown to elicit promising tumor-suppressive effects in preclinical models (Gross et al., 2014), and GDH inhibitors could suppress tumorigenesis in preclinical models of breast cancer (Qing et al., 2012). However, resistance to these treatments inevitably occurs as a consequence of metabolic adaptation to metabolic crisis. For example, induction of pyruvate carboxylase, allowing tumor cells to use glucose-derived pyruvate instead of glutamine for anaplerosis (Cheng et al., 2011), and increased expression of glutamine synthetase (Tardito et al., 2015) also render cancer cell resistance to treatment targeting glutamine metabolism. Interestingly, the findings described in this study suggest that targeting GDH1 enzymatic activity can abrogate metabolic adaptation of glioma cells through an unexplored mechanism, which further highlights the importance of GDH1-targeting treatments in glioma patients. By identifying the binding pocket of a-KG to IKKb,
2 Molecular Cell 76, October 3, 2019
the work also provides crucial information for the potential design of small molecules able to compete with a-KG. The development of this type of small molecule may be utilized for preventing NF-kB activation and GDH1-induced metabolic adaptation in cancer treatment. In addition to cancer cells, glutamine metabolism and production of a-KG have been shown to play critical roles in orchestrating functions and differentiation of immune cells (Johnson et al., 2018; Liu et al., 2017). Thus, it will be important to examine if these regulatory circuits controlled by GDH1 can be used by immune cells for reprogramming their metabolic machineries and can function in response to glucose deprivation condition, such as the tumor microenvironment. Cummins et al. have previously described that a-KG stimulates prolyl hydroxylase 1 (PHD1)-mediated hydroxylation of IKKb on proline 191 to prevent IKKb activation. As a consequence of proline hydroxylation, IKKb fails to phosphorylate IkBa (Cummins et al., 2006; Liu et al., 2017). In contrast to this finding, Wang et al. reported in this new study that
a-KG can stimulate IKKb activation, possibly through metabolite-induced, but not phosphorylation-dependent, structural changes. This surprising finding, for the first time, highlights that a-KG can directly promote enzyme activities without phosphorylation-dependent regulations or serving as a co-factor or substrate. Since Wang et al. identified that GDH1 enzymatic activity is needed for activating IKKb but supplementation of a-KG failed to restore IKKb activation in GDH1-deficient glioma cells, they postulated that local production and distribution of a-KG may differentially impact NF-kB pathway and cellular behavior. In addition to the potential contribution of local production of a-KG, it is legitimate to speculate that a-KG has a dual and opposite role in regulating IKKb due to the differential responses to distinct stimuli, such as hypoxia or low glucose. Nonetheless, it remains unclear whether other proteins interacting with GDH1 can also be affected by a-KG. Can other structural analogs, including fumarate and succinate, antagonize this action as they do in regulating other dioxygenases? Can oncometabolite
Molecular Cell
Previews 2-hydroxyglutarate, an analogous metabolite of a-KG, act in a similar way to stimulate tumor progression, especially in glioma-expressing mutant forms of isocitrate dehydrogenase 1/2 (IDH1/2)? These open questions, if correctly addressed, could reveal new signaling pathways and crosstalk between metabolism and cell functions. Finally, it would be of high interest to understand how this process can reprogram cellular behavior in the NF-kB-dependent manner in response to other metabolic stresses, including hypoxia and acidosis. Overall, these findings uncover a novel cytosolic function of GDH1 in boosting glycolysis besides its original role in glutaminolysis and strongly suggest GDH1 as a potential therapeutic target for gliomas with dual impacts on both glutaminolysis and NF-kB-mediated metabolic program and survival. REFERENCES Cheng, T., Sudderth, J., Yang, C., Mullen, A.R., Jin, E.S., Mate´s, J.M., and DeBerardinis, R.J. (2011). Pyruvate carboxylase is required for glutamine-in-
dependent growth of tumor cells. Proc. Natl. Acad. Sci. USA 108, 8674–8679. Cluntun, A.A., Lukey, M.J., Cerione, R.A., and Locasale, J.W. (2017). Glutamine Metabolism in Cancer: Understanding the Heterogeneity. Trends Cancer 3, 169–180. Cummins, E.P., Berra, E., Comerford, K.M., Ginouves, A., Fitzgerald, K.T., Seeballuck, F., Godson, C., Nielsen, J.E., Moynagh, P., Pouyssegur, J., and Taylor, C.T. (2006). Prolyl hydroxylase-1 negatively regulates IkappaB kinasebeta, giving insight into hypoxia-induced NFkappaB activity. Proc. Natl. Acad. Sci. USA 103, 18154–18159. Gross, M.I., Demo, S.D., Dennison, J.B., Chen, L., Chernov-Rogan, T., Goyal, B., Janes, J.R., Laidig, G.J., Lewis, E.R., Li, J., et al. (2014). Antitumor activity of the glutaminase inhibitor CB-839 in triplenegative breast cancer. Mol. Cancer Ther. 13, 890–901. Johnson, M.O., Wolf, M.M., Madden, M.Z., Andrejeva, G., Sugiura, A., Contreras, D.C., Maseda, D., Liberti, M.V., Paz, K., Kishton, R.J., et al. (2018). Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism. Cell 175, 1780–1795.e19. Li, X., Wenes, M., Romero, P., Huang, S.C., Fendt, S.M., and Ho, P.C. (2019). Navigating metabolic pathways to enhance antitumour immunity and immunotherapy. Nat. Rev. Clin. Oncol. 16, 425–441.
Liu, P.S., Wang, H., Li, X., Chao, T., Teav, T., Christen, S., Di Conza, G., Cheng, W.C., Chou, C.H., Vavakova, M., et al. (2017). a-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat. Immunol. 18, 985–994. Oizel, K., Chauvin, C., Oliver, L., Gratas, C., Geraldo, F., Jarry, U., Scotet, E., Rabe, M., Alves-Guerra, M.C., Teusan, R., et al. (2017). Efficient Mitochondrial Glutamine Targeting Prevails Over Glioblastoma Metabolic Plasticity. Clin. Cancer Res. 23, 6292–6304. Qing, G., Li, B., Vu, A., Skuli, N., Walton, Z.E., Liu, X., Mayes, P.A., Wise, D.R., Thompson, C.B., Maris, J.M., et al. (2012). ATF4 regulates MYCmediated neuroblastoma cell death upon glutamine deprivation. Cancer Cell 22, 631–644. Tardito, S., Oudin, A., Ahmed, S.U., Fack, F., Keunen, O., Zheng, L., Miletic, H., Sakariassen, P.O., Weinstock, A., Wagner, A., et al. (2015). Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutaminerestricted glioblastoma. Nat. Cell Biol. 17, 1556–1568. Wang, X., Liu, R., Qu, X., Yu, H., Chu, H., Zhang, Y., Zhu, W., Wu, X., Gao, H., Tao, B., et al. (2019). a-Ketoglutarate-Activated NF-kB Signaling Promotes Compensatory Glucose Uptake and Brain Tumor Development. Mol. Cell 76, 148–162.
Going in Circles: The Black Box of Circular RNA Immunogenicity Megha G. Basavappa1 and Sara Cherry1,* 1Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA *Correspondence: [email protected] https://doi.org/10.1016/j.molcel.2019.08.027
Two recent papers in Molecular Cell (Chen et al., 2019; Wesselhoeft et al., 2019) have probed the putative immunogenicity of circular RNAs (circRNAs). These studies indicate that the stimulatory capacity of circRNAs depends on factors including the specific RNA, the mode of biogenesis, RNA modifications, cell type, and the means of delivery. Innate immunity relies on the recognition of non-self. This ‘‘sensing’’ is dependent on a growing cadre of proteins that can directly bind to pathogen-associated molecules. In the context of viral infection, these non-self entities are predominately nucleic acids. Recognition results in the activation of antiviral immune responses ranging from the induction of cytokines to direct inhibition of viral repli-
cation by diverse mechanisms. The specific detection of RNA viruses is dependent on a number of pattern recognition receptors (PRRs), including the RIG-Ilike receptors (RLRs) RIG-I and MDA-5 and the endosomal Toll-like receptors (TLR) 3, 7, and 8 (Wu and Chen, 2014). These sensors recognize conserved elements on viral RNAs that were thought to represent unique structures that
distinguished self from non-self. For example, many viral PRRs bind to double-stranded RNAs that are produced as RNA virus replication intermediates. Additional features common to many viral RNAs include 50 triphosphates generated by RNA-dependent RNA polymerases as well as specific stem loops integral for viral translation, transcription termination, and/or packaging.
Molecular Cell 76, October 3, 2019 ª 2019 Published by Elsevier Inc. 3
Previews Fifty Shades of a-Ketoglutarate on Cellular Programming Giusy Di Conza,1,2,3 Chin-Hsien Tsai,1,2,3 and Ping-Chih Ho1,2,* 1Department
of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland Institute for Cancer Research, University of Lausanne, E´palinges, Switzerland 3These authors contributed equally *Correspondence: [email protected] https://doi.org/10.1016/j.molcel.2019.09.002 2Ludwig
High plasticity to utilize different nutrients to adapt metabolic stress is one of the hallmarks for cancer cells. However, the underlying mechanisms by which cancer cells reprogram metabolic machinery in response to metabolic stress remain largely unclear. In this issue of Molecular Cell, Wang et al. (2019) report that glutamate dehydrogenase 1 (GDH1) induces an unconventional regulation of the NF-kB pathway under glucose deprivation, thereby stimulating glycolysis in glioblastomas. Gliomas are extremely aggressive tumors relying on aerobic glycolysis in response to hypoxia. In addition to glucose, glutamine metabolism plays a crucial role to ensure the survival of glioma cells when they experience glucose deprivation (Oizel et al., 2017). Activation of mitochondrial glutamate dehydrogenase 1 (GDH1) stimulates the conversion of glutaminederived glutamate into a-ketoglutarate (a-KG) for supporting energy production. a-KG can be further used for replenishing citrate, an anaplerotic reaction for the tricarboxylic acid (TCA) cycle in highly proliferating cells (Li et al., 2019). In addition, the production of a-KG can impact cellular behaviors by modulating activities of several dioxygenases, such as prolylhydroxylases and DNA demethylases, involved in hypoxic responses and epigenetic reprogramming (Cluntun et al., 2017). While it is clear how the production of a-KG can influence TCA cycle and signaling pathways, it remains unclear whether the generation of a-KG is involved in reprogramming metabolic machineries in cancer cells in response to glucose deprivation. In a study published in this issue of Molecular Cell, Wang et al. showed that activity of GDH1 in low-glucose conditions is needed to promote survival of glioma cells in an a-KG-dependent manner (Wang et al., 2019). In their search of the roles of GDH1 on supporting survival of glioma cells, the authors found that GDH1-depleted cells markedly reduced proliferation under glucose-deprived conditions. In contrast to utilizing gluta-
mine as an alternative nutrient in response to glucose deprivation, GDH1 deficiency led to marked downregulation of glycolytic intermediates and attenuated GLUT1 expression, suggesting that GDH1 may support glycolytic activity of glioma cells in a glucose-deprived condition. By exploiting mass spectrometry (MS) analysis, they further identified that glucose deprivation facilitated the formation of a protein complex containing GDH1, RelA, and the IkB kinase (IKK) complex. When knocking down GDH1 in glioma cells, the authors could suppress NF-kB-driven transcription activity and expression of GLUT1 and impair RelA binding on the promoter region of the GLUT1 gene. Given that NF-kB activation requires degradation of its direct inhibitor IkBa via IKKb-mediated phosphorylation on IkBa, the authors wondered whether the enzymatic activity of GDH1 is needed to activate IKKb and found that GDH1-generated a-KG can directly bind IKKb at residue R140. Intriguingly, binding of a-KG to IKKb stimulated IKKb kinase activity without engaging the conventional IKKb activation process, which relies on phosphorylation of serine 177 and serine 181 residues of IKKb. In addition, overexpressing a mutant form of IKKb (IKKb-R140L), which is unable to bind a-KG, in glioma cells attenuated tumor growth and prevented glucose-deprivation-induced activation of NF-kB and expression of GLUT1 (Figure 1). To further elucidate the underlying mechanism governing the GDH1-RelA
interaction upon glucose deprivation, the authors identified that phosphorylation at serine 384 of GDH1 is indispensable for the GDH1-RelA interaction and NF-kB activation under glucose deprivation. The authors then demonstrated that glucose-starvation-induced activation of AMP-dependent protein kinase (AMPK) causes the phosphorylation of the cytosolic form of GDH1 at serine 384. Importantly, mitochondrial GDH1 could not be phosphorylated by AMPK. These findings highlight a novel role of GDH1 in reprogramming cancer metabolisms that is distinguished from its classical role in the mitochondria. Notably, overexpression of the phosphor-deficient mutant form of GDH1 (GDH1 S384A) drastically attenuated glioma growth in a GLUT1dependent manner in the in vivo murine models. Wang et al. also evaluated the clinical relevance of these findings and demonstrated that the status of serine 384 phosphorylation on GDH1 was positively associated with malignancy grade and poor prognosis in human glioblastoma multiform patients. Together, these results uncover GDH1 pS384 as an independent predictor of prognosis in glioblastoma patients. Pediatric and adult glioblastoma are aggressive and incurable diseases, causing a high percentage of cancer mortality. Current therapy includes surgical resection followed by radiotherapy in combination with adjuvant chemotherapy, but the overall survival of these patients is very poor. Given the dependence of cancer cells on glutamine metabolism,
Molecular Cell 76, October 3, 2019 ª 2019 Elsevier Inc. 1
Molecular Cell
Previews
Figure 1. GDH-Mediated a-Ketoglutarate Production Elicits Compensatory Glycolysis in Response to Glucose Deprivation
Once entering cells, glutamine can be converted to a-KG through glutaminolysis mediated by GLS and GDH. a-KG either enters the TCA cycle to produce energy for cell growth or contributes to the metabolic recycling of ammonia for biomass production. Moreover, a-KG is a substrate of dioxygenase enzymes in the regulation of histone and DNA methylation or PHD-dependent IKK post-translational modification. In addition to that, in low-glucose conditions, cytosolic GDHderived a-KG can bind and activate IKKb, promoting NF-kB activation, Glut1 expression, and glycolysis. This regulation of IKKb is distinct from phosphorylationmediated activation and requires the interaction of phosphorylated GDH at serine 384.
targeted therapies have already been developed against glutamine metabolism, from glutamine uptake to glutamine-catalyzed enzymes. Inhibition of glutaminase (GLS) with CB-839 has been shown to elicit promising tumor-suppressive effects in preclinical models (Gross et al., 2014), and GDH inhibitors could suppress tumorigenesis in preclinical models of breast cancer (Qing et al., 2012). However, resistance to these treatments inevitably occurs as a consequence of metabolic adaptation to metabolic crisis. For example, induction of pyruvate carboxylase, allowing tumor cells to use glucose-derived pyruvate instead of glutamine for anaplerosis (Cheng et al., 2011), and increased expression of glutamine synthetase (Tardito et al., 2015) also render cancer cell resistance to treatment targeting glutamine metabolism. Interestingly, the findings described in this study suggest that targeting GDH1 enzymatic activity can abrogate metabolic adaptation of glioma cells through an unexplored mechanism, which further highlights the importance of GDH1-targeting treatments in glioma patients. By identifying the binding pocket of a-KG to IKKb,
2 Molecular Cell 76, October 3, 2019
the work also provides crucial information for the potential design of small molecules able to compete with a-KG. The development of this type of small molecule may be utilized for preventing NF-kB activation and GDH1-induced metabolic adaptation in cancer treatment. In addition to cancer cells, glutamine metabolism and production of a-KG have been shown to play critical roles in orchestrating functions and differentiation of immune cells (Johnson et al., 2018; Liu et al., 2017). Thus, it will be important to examine if these regulatory circuits controlled by GDH1 can be used by immune cells for reprogramming their metabolic machineries and can function in response to glucose deprivation condition, such as the tumor microenvironment. Cummins et al. have previously described that a-KG stimulates prolyl hydroxylase 1 (PHD1)-mediated hydroxylation of IKKb on proline 191 to prevent IKKb activation. As a consequence of proline hydroxylation, IKKb fails to phosphorylate IkBa (Cummins et al., 2006; Liu et al., 2017). In contrast to this finding, Wang et al. reported in this new study that
a-KG can stimulate IKKb activation, possibly through metabolite-induced, but not phosphorylation-dependent, structural changes. This surprising finding, for the first time, highlights that a-KG can directly promote enzyme activities without phosphorylation-dependent regulations or serving as a co-factor or substrate. Since Wang et al. identified that GDH1 enzymatic activity is needed for activating IKKb but supplementation of a-KG failed to restore IKKb activation in GDH1-deficient glioma cells, they postulated that local production and distribution of a-KG may differentially impact NF-kB pathway and cellular behavior. In addition to the potential contribution of local production of a-KG, it is legitimate to speculate that a-KG has a dual and opposite role in regulating IKKb due to the differential responses to distinct stimuli, such as hypoxia or low glucose. Nonetheless, it remains unclear whether other proteins interacting with GDH1 can also be affected by a-KG. Can other structural analogs, including fumarate and succinate, antagonize this action as they do in regulating other dioxygenases? Can oncometabolite
Molecular Cell
Previews 2-hydroxyglutarate, an analogous metabolite of a-KG, act in a similar way to stimulate tumor progression, especially in glioma-expressing mutant forms of isocitrate dehydrogenase 1/2 (IDH1/2)? These open questions, if correctly addressed, could reveal new signaling pathways and crosstalk between metabolism and cell functions. Finally, it would be of high interest to understand how this process can reprogram cellular behavior in the NF-kB-dependent manner in response to other metabolic stresses, including hypoxia and acidosis. Overall, these findings uncover a novel cytosolic function of GDH1 in boosting glycolysis besides its original role in glutaminolysis and strongly suggest GDH1 as a potential therapeutic target for gliomas with dual impacts on both glutaminolysis and NF-kB-mediated metabolic program and survival. REFERENCES Cheng, T., Sudderth, J., Yang, C., Mullen, A.R., Jin, E.S., Mate´s, J.M., and DeBerardinis, R.J. (2011). Pyruvate carboxylase is required for glutamine-in-
dependent growth of tumor cells. Proc. Natl. Acad. Sci. USA 108, 8674–8679. Cluntun, A.A., Lukey, M.J., Cerione, R.A., and Locasale, J.W. (2017). Glutamine Metabolism in Cancer: Understanding the Heterogeneity. Trends Cancer 3, 169–180. Cummins, E.P., Berra, E., Comerford, K.M., Ginouves, A., Fitzgerald, K.T., Seeballuck, F., Godson, C., Nielsen, J.E., Moynagh, P., Pouyssegur, J., and Taylor, C.T. (2006). Prolyl hydroxylase-1 negatively regulates IkappaB kinasebeta, giving insight into hypoxia-induced NFkappaB activity. Proc. Natl. Acad. Sci. USA 103, 18154–18159. Gross, M.I., Demo, S.D., Dennison, J.B., Chen, L., Chernov-Rogan, T., Goyal, B., Janes, J.R., Laidig, G.J., Lewis, E.R., Li, J., et al. (2014). Antitumor activity of the glutaminase inhibitor CB-839 in triplenegative breast cancer. Mol. Cancer Ther. 13, 890–901. Johnson, M.O., Wolf, M.M., Madden, M.Z., Andrejeva, G., Sugiura, A., Contreras, D.C., Maseda, D., Liberti, M.V., Paz, K., Kishton, R.J., et al. (2018). Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism. Cell 175, 1780–1795.e19. Li, X., Wenes, M., Romero, P., Huang, S.C., Fendt, S.M., and Ho, P.C. (2019). Navigating metabolic pathways to enhance antitumour immunity and immunotherapy. Nat. Rev. Clin. Oncol. 16, 425–441.
Liu, P.S., Wang, H., Li, X., Chao, T., Teav, T., Christen, S., Di Conza, G., Cheng, W.C., Chou, C.H., Vavakova, M., et al. (2017). a-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat. Immunol. 18, 985–994. Oizel, K., Chauvin, C., Oliver, L., Gratas, C., Geraldo, F., Jarry, U., Scotet, E., Rabe, M., Alves-Guerra, M.C., Teusan, R., et al. (2017). Efficient Mitochondrial Glutamine Targeting Prevails Over Glioblastoma Metabolic Plasticity. Clin. Cancer Res. 23, 6292–6304. Qing, G., Li, B., Vu, A., Skuli, N., Walton, Z.E., Liu, X., Mayes, P.A., Wise, D.R., Thompson, C.B., Maris, J.M., et al. (2012). ATF4 regulates MYCmediated neuroblastoma cell death upon glutamine deprivation. Cancer Cell 22, 631–644. Tardito, S., Oudin, A., Ahmed, S.U., Fack, F., Keunen, O., Zheng, L., Miletic, H., Sakariassen, P.O., Weinstock, A., Wagner, A., et al. (2015). Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutaminerestricted glioblastoma. Nat. Cell Biol. 17, 1556–1568. Wang, X., Liu, R., Qu, X., Yu, H., Chu, H., Zhang, Y., Zhu, W., Wu, X., Gao, H., Tao, B., et al. (2019). a-Ketoglutarate-Activated NF-kB Signaling Promotes Compensatory Glucose Uptake and Brain Tumor Development. Mol. Cell 76, 148–162.
Going in Circles: The Black Box of Circular RNA Immunogenicity Megha G. Basavappa1 and Sara Cherry1,* 1Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA *Correspondence: [email protected] https://doi.org/10.1016/j.molcel.2019.08.027
Two recent papers in Molecular Cell (Chen et al., 2019; Wesselhoeft et al., 2019) have probed the putative immunogenicity of circular RNAs (circRNAs). These studies indicate that the stimulatory capacity of circRNAs depends on factors including the specific RNA, the mode of biogenesis, RNA modifications, cell type, and the means of delivery. Innate immunity relies on the recognition of non-self. This ‘‘sensing’’ is dependent on a growing cadre of proteins that can directly bind to pathogen-associated molecules. In the context of viral infection, these non-self entities are predominately nucleic acids. Recognition results in the activation of antiviral immune responses ranging from the induction of cytokines to direct inhibition of viral repli-
cation by diverse mechanisms. The specific detection of RNA viruses is dependent on a number of pattern recognition receptors (PRRs), including the RIG-Ilike receptors (RLRs) RIG-I and MDA-5 and the endosomal Toll-like receptors (TLR) 3, 7, and 8 (Wu and Chen, 2014). These sensors recognize conserved elements on viral RNAs that were thought to represent unique structures that
distinguished self from non-self. For example, many viral PRRs bind to double-stranded RNAs that are produced as RNA virus replication intermediates. Additional features common to many viral RNAs include 50 triphosphates generated by RNA-dependent RNA polymerases as well as specific stem loops integral for viral translation, transcription termination, and/or packaging.
Molecular Cell 76, October 3, 2019 ª 2019 Published by Elsevier Inc. 3