Pub Date : 2025-09-30DOI: 10.1126/scisignal.ado8924
Irene Estadella, María Navarro-Pérez, Magalí Colomer-Molera, Michael L. Dustin, Alexander Sorkin, Jesusa Capera, Antonio Felipe
The voltage-gated potassium channel Kv1.3 contributes to action potential conduction in sensory neurons and to sustained increases in cytoplasmic Ca2+ that activate immune cells. Here, we found that two distinct endocytosis-inducing stimuli acted through the same residues in Kv1.3 to control surface abundance and activity of the channel. Upon stimulation of the growth factor receptor EGFR, which stimulates Tyr-directed kinases and is important in neuronal differentiation, or of the Ser/Thr kinase PKC, which participates in the down-regulation of inflammatory responses, Kv1.3 underwent ubiquitination-dependent endocytosis that routed channel proteins to lysosomes for degradation. We mapped two lysine clusters in the N and C termini of Kv1.3, both of which became ubiquitinated upon activation of either Tyr or Ser/Thr kinases and whose combined mutation had an additive effect in reducing ubiquitination and endocytosis. Manipulations that prevented the ubiquitination or decreased the endocytosis of Kv1.3 resulted in increased Kv1.3 abundance at the immunological synapse and activity in primary human T cells. Prolonged channel accumulation at this location would be expected to increase Kv1.3-dependent leukocyte activation and lead to chronic inflammatory pathologies. Thus, ubiquitination fine-tunes cell biology by inducing the endocytosis and turnover of Kv1.3 in response to biological stimuli and insults.
{"title":"Molecular determinants for the endocytosis of the voltage-gated K+ channel Kv1.3","authors":"Irene Estadella, María Navarro-Pérez, Magalí Colomer-Molera, Michael L. Dustin, Alexander Sorkin, Jesusa Capera, Antonio Felipe","doi":"10.1126/scisignal.ado8924","DOIUrl":"10.1126/scisignal.ado8924","url":null,"abstract":"<div >The voltage-gated potassium channel Kv1.3 contributes to action potential conduction in sensory neurons and to sustained increases in cytoplasmic Ca<sup>2+</sup> that activate immune cells. Here, we found that two distinct endocytosis-inducing stimuli acted through the same residues in Kv1.3 to control surface abundance and activity of the channel. Upon stimulation of the growth factor receptor EGFR, which stimulates Tyr-directed kinases and is important in neuronal differentiation, or of the Ser/Thr kinase PKC, which participates in the down-regulation of inflammatory responses, Kv1.3 underwent ubiquitination-dependent endocytosis that routed channel proteins to lysosomes for degradation. We mapped two lysine clusters in the N and C termini of Kv1.3, both of which became ubiquitinated upon activation of either Tyr or Ser/Thr kinases and whose combined mutation had an additive effect in reducing ubiquitination and endocytosis. Manipulations that prevented the ubiquitination or decreased the endocytosis of Kv1.3 resulted in increased Kv1.3 abundance at the immunological synapse and activity in primary human T cells. Prolonged channel accumulation at this location would be expected to increase Kv1.3-dependent leukocyte activation and lead to chronic inflammatory pathologies. Thus, ubiquitination fine-tunes cell biology by inducing the endocytosis and turnover of Kv1.3 in response to biological stimuli and insults.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 906","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-30DOI: 10.1126/scisignal.adu7145
Priya S. Hibshman, Clint A. Stalnecker, Jeffrey A. Klomp, Kristina Drizyte-Miller, Jennifer E. Klomp, A. Cole Edwards, Lily M. Pita, Richard G. Hodge, J. Nathaniel Diehl, Ryan D. Mouery, Brandon L. Mouery, Kayla R. Snare, Andrew M. Waters, Sen Peng, Natalie K. Barker, Mariaelena Pierobon, Naim U. Rashid, Nhan L. Tran, Laura A. Herring, Lee M. Graves, Emanuel F. Petricoin III, Kirsten L. Bryant, Adrienne D. Cox, Channing J. Der
Of the thousands of genes and substrates identified in KRAS-mutant signaling networks in pancreatic ductal adenocarcinoma (PDAC), more than 200 are transcription factors, implying extensive and complex transcriptional regulation. However, we observed that genetic suppression of the transcription factor MYC alone was sufficient to phenocopy the effect of KRAS suppression in signaling, growth, and metabolic processes in PDAC cells. We determined the gene transcription changes caused by acute suppression of MYC function in KRAS-mutant PDAC cell lines and performed dependency map and pathway analyses on the affected gene sets. The expression of 1685 genes was increased upon suppression of MYC, and this gene set may comprise the bulk of the MYC-regulated genes essential for PDAC growth. In contrast, the 1325 genes whose expression was inhibited may comprise a compensatory response to oncogenic stress, mediated in part by the GTPase RHO. MYC-dependent transcriptional activity was largely ERK dependent, and almost one-third of ERK-regulated genes were also regulated by MYC in PDAC cells. Furthermore, chemical proteomic profiling revealed MYC-regulated protein kinases that can be targeted therapeutically. Together, these data provide a molecular portrait of MYC-dependent signaling that encompasses potentially exploitable mechanisms for treating PDAC.
{"title":"Defining the MYC-regulated transcriptome and kinome that support KRAS- and ERK-dependent growth of pancreatic cancer","authors":"Priya S. Hibshman, Clint A. Stalnecker, Jeffrey A. Klomp, Kristina Drizyte-Miller, Jennifer E. Klomp, A. Cole Edwards, Lily M. Pita, Richard G. Hodge, J. Nathaniel Diehl, Ryan D. Mouery, Brandon L. Mouery, Kayla R. Snare, Andrew M. Waters, Sen Peng, Natalie K. Barker, Mariaelena Pierobon, Naim U. Rashid, Nhan L. Tran, Laura A. Herring, Lee M. Graves, Emanuel F. Petricoin III, Kirsten L. Bryant, Adrienne D. Cox, Channing J. Der","doi":"10.1126/scisignal.adu7145","DOIUrl":"10.1126/scisignal.adu7145","url":null,"abstract":"<div >Of the thousands of genes and substrates identified in KRAS-mutant signaling networks in pancreatic ductal adenocarcinoma (PDAC), more than 200 are transcription factors, implying extensive and complex transcriptional regulation. However, we observed that genetic suppression of the transcription factor MYC alone was sufficient to phenocopy the effect of KRAS suppression in signaling, growth, and metabolic processes in PDAC cells. We determined the gene transcription changes caused by acute suppression of MYC function in <i>KRAS</i>-mutant PDAC cell lines and performed dependency map and pathway analyses on the affected gene sets. The expression of 1685 genes was increased upon suppression of MYC, and this gene set may comprise the bulk of the MYC-regulated genes essential for PDAC growth. In contrast, the 1325 genes whose expression was inhibited may comprise a compensatory response to oncogenic stress, mediated in part by the GTPase RHO. MYC-dependent transcriptional activity was largely ERK dependent, and almost one-third of ERK-regulated genes were also regulated by MYC in PDAC cells. Furthermore, chemical proteomic profiling revealed MYC-regulated protein kinases that can be targeted therapeutically. Together, these data provide a molecular portrait of MYC-dependent signaling that encompasses potentially exploitable mechanisms for treating PDAC.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 906","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adu7145","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-23DOI: 10.1126/scisignal.adr3177
Gina Papadopoulou, Dimitrios Valakos, Ioanna Polydouri, Afroditi Moulara, Giannis Vatsellas, Stefano Angiari, Marah C. Runtsch, Marc Foretz, Benoit Viollet, Antonino Cassotta, Luke A. J. O’Neill, Georgina Xanthou
Metabolic reprogramming controls protective and pathogenic T helper 17 (TH17) cell responses. When naïve T cells are differentiated into TH17 cells in vitro, the presence of the cytokine activin A promotes their maturation into a nonpathogenic state. Here, we found that nonpathogenic TH17 cells induced by activin A displayed reduced aerobic glycolysis and increased oxidative phosphorylation (OXPHOS). In response to activin A, signaling through the adenosine A2A receptor (A2AR) and AMP-activated protein kinase (AMPK) enhanced OXPHOS and reprogrammed pathogenic TH17 cells toward nonpathogenic states that did not induce central nervous system autoimmunity in a mouse model of multiple sclerosis. In pathogenic TH17 cells, the transcriptional coactivator p300/CBP-associated factor (PCAF) increased acetylation at histone 3 Lys9 (H3K9ac) of genes involved in aerobic glycolysis and TH17 pathogenic programs. In contrast, in nonpathogenic activin A–treated TH17 cells, AMPK signaling suppressed PCAF-mediated H3K9ac modification of genes involved in aerobic metabolism and enhanced H3K9ac modification of genes involved in OXPHOS and nonpathogenic TH17 programs. Together, our findings uncover A2AR-AMPK signaling as a central metabolic checkpoint that suppresses TH17 cell pathogenicity.
{"title":"Adenosine 2A receptor–dependent activation of AMPK represses TH17 cell pathogenicity through epigenetic and metabolic reprogramming","authors":"Gina Papadopoulou, Dimitrios Valakos, Ioanna Polydouri, Afroditi Moulara, Giannis Vatsellas, Stefano Angiari, Marah C. Runtsch, Marc Foretz, Benoit Viollet, Antonino Cassotta, Luke A. J. O’Neill, Georgina Xanthou","doi":"10.1126/scisignal.adr3177","DOIUrl":"10.1126/scisignal.adr3177","url":null,"abstract":"<div >Metabolic reprogramming controls protective and pathogenic T helper 17 (T<sub>H</sub>17) cell responses. When naïve T cells are differentiated into T<sub>H</sub>17 cells in vitro, the presence of the cytokine activin A promotes their maturation into a nonpathogenic state. Here, we found that nonpathogenic T<sub>H</sub>17 cells induced by activin A displayed reduced aerobic glycolysis and increased oxidative phosphorylation (OXPHOS). In response to activin A, signaling through the adenosine A<sub>2A</sub> receptor (A<sub>2A</sub>R) and AMP-activated protein kinase (AMPK) enhanced OXPHOS and reprogrammed pathogenic T<sub>H</sub>17 cells toward nonpathogenic states that did not induce central nervous system autoimmunity in a mouse model of multiple sclerosis. In pathogenic T<sub>H</sub>17 cells, the transcriptional coactivator p300/CBP-associated factor (PCAF) increased acetylation at histone 3 Lys<sup>9</sup> (H3K9ac) of genes involved in aerobic glycolysis and T<sub>H</sub>17 pathogenic programs. In contrast, in nonpathogenic activin A–treated T<sub>H</sub>17 cells, AMPK signaling suppressed PCAF-mediated H3K9ac modification of genes involved in aerobic metabolism and enhanced H3K9ac modification of genes involved in OXPHOS and nonpathogenic T<sub>H</sub>17 programs. Together, our findings uncover A<sub>2A</sub>R-AMPK signaling as a central metabolic checkpoint that suppresses T<sub>H</sub>17 cell pathogenicity.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 905","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-23DOI: 10.1126/scisignal.aec3820
Wei Wong
Mitochondrial stress drives brown fat whitening through a pathway involving reduced nuclear stiffness.
线粒体压力通过降低核硬度的途径驱动棕色脂肪变白。
{"title":"Softer nuclei for whiter brown fat","authors":"Wei Wong","doi":"10.1126/scisignal.aec3820","DOIUrl":"10.1126/scisignal.aec3820","url":null,"abstract":"<div >Mitochondrial stress drives brown fat whitening through a pathway involving reduced nuclear stiffness.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 905","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-23DOI: 10.1126/scisignal.adk4594
Hanin Alamir, Carissa C. W. Wong, Amal Alsubaiti, Grace L. Edmunds, Maryam Alismail, Lan Huynh, Yiwei Shi, Philip A. Lewis, Tressan Grant, Safaa Alsulaimani, James Boyd, Christopher J. Holland, David J. Morgan, Awen M. Gallimore, Christoph Wülfing
TIM3 is a coregulatory receptor that is highly abundant on multiple immune cell types, including T cells in response to prolonged exposure to antigen, and it marks functionally suppressed cytotoxic T lymphocytes (CTLs) in the tumor microenvironment. TIM3 exhibits inhibitory function in vivo but paradoxically has costimulatory T cell signaling capability in vitro. Here, we found that TIM3 directly inhibited the function of murine and human CTLs in direct interaction with target tumor cell spheroids. TIM3 regulated the ability of suppressed CTLs to polarize their actin cytoskeleton as a required step in cytolysis. Whereas the expression of the proposed TIM3 ligands CEACAM1 and galectin 9 in trans on target tumor cells enhanced TIM3 function, expression of CEACAM1 in cis on CTLs had the opposite effect. TIM3 functioned as an inhibitory receptor on spheroid-suppressed CTLs but not on active CTLs in a two-dimensional tissue culture model. Together, these data suggest that TIM3 enhances T cell function, serving as either a coinhibitory or costimulatory receptor depending on the functional context of the T cell on which it is expressed.
{"title":"TIM3 is a context-dependent coregulator of cytotoxic T cell function","authors":"Hanin Alamir, Carissa C. W. Wong, Amal Alsubaiti, Grace L. Edmunds, Maryam Alismail, Lan Huynh, Yiwei Shi, Philip A. Lewis, Tressan Grant, Safaa Alsulaimani, James Boyd, Christopher J. Holland, David J. Morgan, Awen M. Gallimore, Christoph Wülfing","doi":"10.1126/scisignal.adk4594","DOIUrl":"10.1126/scisignal.adk4594","url":null,"abstract":"<div >TIM3 is a coregulatory receptor that is highly abundant on multiple immune cell types, including T cells in response to prolonged exposure to antigen, and it marks functionally suppressed cytotoxic T lymphocytes (CTLs) in the tumor microenvironment. TIM3 exhibits inhibitory function in vivo but paradoxically has costimulatory T cell signaling capability in vitro. Here, we found that TIM3 directly inhibited the function of murine and human CTLs in direct interaction with target tumor cell spheroids. TIM3 regulated the ability of suppressed CTLs to polarize their actin cytoskeleton as a required step in cytolysis. Whereas the expression of the proposed TIM3 ligands CEACAM1 and galectin 9 in trans on target tumor cells enhanced TIM3 function, expression of CEACAM1 in cis on CTLs had the opposite effect. TIM3 functioned as an inhibitory receptor on spheroid-suppressed CTLs but not on active CTLs in a two-dimensional tissue culture model. Together, these data suggest that TIM3 enhances T cell function, serving as either a coinhibitory or costimulatory receptor depending on the functional context of the T cell on which it is expressed.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 905","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-23DOI: 10.1126/scisignal.adk4594
Hanin Alamir, Carissa C. W. Wong, Amal Alsubaiti, Grace L. Edmunds, Maryam Alismail, Lan Huynh, Yiwei Shi, Philip A. Lewis, Tressan Grant, Safaa Alsulaimani, James Boyd, Christopher J. Holland, David J. Morgan, Awen M. Gallimore, Christoph Wülfing
TIM3 is a coregulatory receptor that is highly abundant on multiple immune cell types, including T cells in response to prolonged exposure to antigen, and it marks functionally suppressed cytotoxic T lymphocytes (CTLs) in the tumor microenvironment. TIM3 exhibits inhibitory function in vivo but paradoxically has costimulatory T cell signaling capability in vitro. Here, we found that TIM3 directly inhibited the function of murine and human CTLs in direct interaction with target tumor cell spheroids. TIM3 regulated the ability of suppressed CTLs to polarize their actin cytoskeleton as a required step in cytolysis. Whereas the expression of the proposed TIM3 ligands CEACAM1 and galectin 9 in trans on target tumor cells enhanced TIM3 function, expression of CEACAM1 in cis on CTLs had the opposite effect. TIM3 functioned as an inhibitory receptor on spheroid-suppressed CTLs but not on active CTLs in a two-dimensional tissue culture model. Together, these data suggest that TIM3 enhances T cell function, serving as either a coinhibitory or costimulatory receptor depending on the functional context of the T cell on which it is expressed.
{"title":"TIM3 is a context-dependent coregulator of cytotoxic T cell function","authors":"Hanin Alamir, Carissa C. W. Wong, Amal Alsubaiti, Grace L. Edmunds, Maryam Alismail, Lan Huynh, Yiwei Shi, Philip A. Lewis, Tressan Grant, Safaa Alsulaimani, James Boyd, Christopher J. Holland, David J. Morgan, Awen M. Gallimore, Christoph Wülfing","doi":"10.1126/scisignal.adk4594","DOIUrl":"10.1126/scisignal.adk4594","url":null,"abstract":"<div >TIM3 is a coregulatory receptor that is highly abundant on multiple immune cell types, including T cells in response to prolonged exposure to antigen, and it marks functionally suppressed cytotoxic T lymphocytes (CTLs) in the tumor microenvironment. TIM3 exhibits inhibitory function in vivo but paradoxically has costimulatory T cell signaling capability in vitro. Here, we found that TIM3 directly inhibited the function of murine and human CTLs in direct interaction with target tumor cell spheroids. TIM3 regulated the ability of suppressed CTLs to polarize their actin cytoskeleton as a required step in cytolysis. Whereas the expression of the proposed TIM3 ligands CEACAM1 and galectin 9 in trans on target tumor cells enhanced TIM3 function, expression of CEACAM1 in cis on CTLs had the opposite effect. TIM3 functioned as an inhibitory receptor on spheroid-suppressed CTLs but not on active CTLs in a two-dimensional tissue culture model. Together, these data suggest that TIM3 enhances T cell function, serving as either a coinhibitory or costimulatory receptor depending on the functional context of the T cell on which it is expressed.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 905","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-23DOI: 10.1126/scisignal.aec3820
Wei Wong
Mitochondrial stress drives brown fat whitening through a pathway involving reduced nuclear stiffness.
线粒体压力通过降低核硬度的途径驱动棕色脂肪变白。
{"title":"Softer nuclei for whiter brown fat","authors":"Wei Wong","doi":"10.1126/scisignal.aec3820","DOIUrl":"10.1126/scisignal.aec3820","url":null,"abstract":"<div >Mitochondrial stress drives brown fat whitening through a pathway involving reduced nuclear stiffness.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 905","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-23DOI: 10.1126/scisignal.adr3177
Gina Papadopoulou, Dimitrios Valakos, Ioanna Polydouri, Afroditi Moulara, Giannis Vatsellas, Stefano Angiari, Marah C. Runtsch, Marc Foretz, Benoit Viollet, Antonino Cassotta, Luke A. J. O’Neill, Georgina Xanthou
Metabolic reprogramming controls protective and pathogenic T helper 17 (TH17) cell responses. When naïve T cells are differentiated into TH17 cells in vitro, the presence of the cytokine activin A promotes their maturation into a nonpathogenic state. Here, we found that nonpathogenic TH17 cells induced by activin A displayed reduced aerobic glycolysis and increased oxidative phosphorylation (OXPHOS). In response to activin A, signaling through the adenosine A2A receptor (A2AR) and AMP-activated protein kinase (AMPK) enhanced OXPHOS and reprogrammed pathogenic TH17 cells toward nonpathogenic states that did not induce central nervous system autoimmunity in a mouse model of multiple sclerosis. In pathogenic TH17 cells, the transcriptional coactivator p300/CBP-associated factor (PCAF) increased acetylation at histone 3 Lys9 (H3K9ac) of genes involved in aerobic glycolysis and TH17 pathogenic programs. In contrast, in nonpathogenic activin A–treated TH17 cells, AMPK signaling suppressed PCAF-mediated H3K9ac modification of genes involved in aerobic metabolism and enhanced H3K9ac modification of genes involved in OXPHOS and nonpathogenic TH17 programs. Together, our findings uncover A2AR-AMPK signaling as a central metabolic checkpoint that suppresses TH17 cell pathogenicity.
{"title":"Adenosine 2A receptor–dependent activation of AMPK represses TH17 cell pathogenicity through epigenetic and metabolic reprogramming","authors":"Gina Papadopoulou, Dimitrios Valakos, Ioanna Polydouri, Afroditi Moulara, Giannis Vatsellas, Stefano Angiari, Marah C. Runtsch, Marc Foretz, Benoit Viollet, Antonino Cassotta, Luke A. J. O’Neill, Georgina Xanthou","doi":"10.1126/scisignal.adr3177","DOIUrl":"10.1126/scisignal.adr3177","url":null,"abstract":"<div >Metabolic reprogramming controls protective and pathogenic T helper 17 (T<sub>H</sub>17) cell responses. When naïve T cells are differentiated into T<sub>H</sub>17 cells in vitro, the presence of the cytokine activin A promotes their maturation into a nonpathogenic state. Here, we found that nonpathogenic T<sub>H</sub>17 cells induced by activin A displayed reduced aerobic glycolysis and increased oxidative phosphorylation (OXPHOS). In response to activin A, signaling through the adenosine A<sub>2A</sub> receptor (A<sub>2A</sub>R) and AMP-activated protein kinase (AMPK) enhanced OXPHOS and reprogrammed pathogenic T<sub>H</sub>17 cells toward nonpathogenic states that did not induce central nervous system autoimmunity in a mouse model of multiple sclerosis. In pathogenic T<sub>H</sub>17 cells, the transcriptional coactivator p300/CBP-associated factor (PCAF) increased acetylation at histone 3 Lys<sup>9</sup> (H3K9ac) of genes involved in aerobic glycolysis and T<sub>H</sub>17 pathogenic programs. In contrast, in nonpathogenic activin A–treated T<sub>H</sub>17 cells, AMPK signaling suppressed PCAF-mediated H3K9ac modification of genes involved in aerobic metabolism and enhanced H3K9ac modification of genes involved in OXPHOS and nonpathogenic T<sub>H</sub>17 programs. Together, our findings uncover A<sub>2A</sub>R-AMPK signaling as a central metabolic checkpoint that suppresses T<sub>H</sub>17 cell pathogenicity.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 905","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-16DOI: 10.1126/scisignal.adx5186
Nancy E. Sealover, Bridget A. Finniff, Jacob M. Hughes, Erin Sheffels, Hyun Lee, Joseph P. LaMorte, Vainavi Gambhir, Zaria Beckley, Amanda Linke, Matthew D. Wilkerson, Marielle E. Yohe, Robert L. Kortum
Mutated RAS proteins activate downstream effector pathways (RAF-MEK-ERK and PI3K-AKT) to drive oncogenic transformation and progression. Because RAS family members differentially engage these pathways, combined inhibition of both pathways is required to effectively treat RAS-mutated cancers. Here, we found that this was due to signaling contributed by wild-type RAS family members that activated an effector pathway that was poorly engaged by the mutant RAS family member. Wild-type KRAS and NRAS promoted RAF-MEK-ERK signaling in cells expressing mutant HRAS, whereas wild-type HRAS and NRAS promoted PI3K-AKT signaling in cells expressing mutant KRAS. Combining inhibitors targeting the poorly engaged RAS effector pathways with inhibitors targeting the mutant RAS resulted in synergistic cytotoxicity in a manner that depended on wild-type RAS expression. The farnesyltransferase inhibitor tipifarnib blocked mutant HRAS-PI3K signaling and synergized with MEK inhibitors in HRAS-mutated cells, whereas KRASG12C inhibitors blocked mutant KRAS-MEK signaling and synergized with PI3K inhibitors in KRASG12C-mutated cells. Synergy was abolished in MEFs lacking all RAS proteins and in cancer cell lines in which nonmutated RAS family members were deleted. Our data highlight the critical role of wild-type RAS family members in supporting mutant RAS signaling and its importance as a therapeutic cotarget in RAS-mutated cancers.
{"title":"Wild-type RAS signaling is an essential therapeutic target in RAS-mutated cancers","authors":"Nancy E. Sealover, Bridget A. Finniff, Jacob M. Hughes, Erin Sheffels, Hyun Lee, Joseph P. LaMorte, Vainavi Gambhir, Zaria Beckley, Amanda Linke, Matthew D. Wilkerson, Marielle E. Yohe, Robert L. Kortum","doi":"10.1126/scisignal.adx5186","DOIUrl":"10.1126/scisignal.adx5186","url":null,"abstract":"<div >Mutated RAS proteins activate downstream effector pathways (RAF-MEK-ERK and PI3K-AKT) to drive oncogenic transformation and progression. Because RAS family members differentially engage these pathways, combined inhibition of both pathways is required to effectively treat <i>RAS</i>-mutated cancers. Here, we found that this was due to signaling contributed by wild-type RAS family members that activated an effector pathway that was poorly engaged by the mutant RAS family member. Wild-type KRAS and NRAS promoted RAF-MEK-ERK signaling in cells expressing mutant HRAS, whereas wild-type HRAS and NRAS promoted PI3K-AKT signaling in cells expressing mutant KRAS. Combining inhibitors targeting the poorly engaged RAS effector pathways with inhibitors targeting the mutant RAS resulted in synergistic cytotoxicity in a manner that depended on wild-type RAS expression. The farnesyltransferase inhibitor tipifarnib blocked mutant HRAS-PI3K signaling and synergized with MEK inhibitors in <i>HRAS</i>-mutated cells, whereas KRAS<sup>G12C</sup> inhibitors blocked mutant KRAS-MEK signaling and synergized with PI3K inhibitors in <i>KRAS<sup>G12C</sup></i>-mutated cells. Synergy was abolished in MEFs lacking all RAS proteins and in cancer cell lines in which nonmutated RAS family members were deleted. Our data highlight the critical role of wild-type RAS family members in supporting mutant RAS signaling and its importance as a therapeutic cotarget in <i>RAS</i>-mutated cancers.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 904","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145076456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-16DOI: 10.1126/scisignal.adq8778
Lucie Fallone, Kévin Pouxvielh, Laure Arbez, Noëmi Rousseaux, Louis Picq, Annabelle Drouillard, Anne-Laure Mathieu, Anaïs Nombel, Sarah Benezech, Emilie Bourdonnay, Sophie Degouve, Pierre Machy, Erwan Mortier, Eléonore Bouscasse, Karima Chaoui, Bernard Malissen, Anne Gonzalez de Peredo, Romain Roncagalli, Thierry Walzer, Antoine Marçais
The multiprotein complex mTORC1 is essential for the increase in protein synthesis and bioenergetic metabolism that supports the proliferation of many cell types, including natural killer (NK) cells, which are important innate effectors of the antitumoral response. Here, we investigated the mechanisms of mTORC1 activation in NK cells by interleukin-15 (IL-15) and IL-18, which promote NK cell function and are components of a cytokine cocktail used to preactivate NK cells for cancer immunotherapy. Through genetic and pharmacological approaches, we showed that IL-15 activated mTORC1 through the PI3K/Akt/ERK pathway, whereas IL-18 signaled through the p38 effectors MK2 and MK3 in both murine and human primary NK cells. Both pathways synergized to promote NK cell proliferation and effector functions in an mTORC1-dependent manner. Moreover, both pathways operated independently of the inhibitor TSC and the activator Rheb, revealing a noncanonical mode of mTORC1 activation by cytokines. Treating mice with IL-15 and IL-18 in combination led to increased NK cell numbers and improved antitumoral activity, suggesting that this cytokine combination could be exploited to enhance NK cell potential in therapeutic settings.
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