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.
{"title":"Interleukins 15 and 18 synergistically prime the antitumor function of natural killer cells through noncanonical activation of mTORC1","authors":"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","doi":"10.1126/scisignal.adq8778","DOIUrl":"10.1126/scisignal.adq8778","url":null,"abstract":"<div >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.</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":"https://www.science.org/doi/reader/10.1126/scisignal.adq8778","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145076391","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 : 2025-09-09DOI: 10.1126/scisignal.ado9243
Bryson C. Okeoma, Hussein Kaddour, Wasifa Naushad, Victor Paromov, Ashok Chaudhary, Alessio Noghero, Jack T. Stapleton, Chioma M. Okeoma
Replication of HIV-1 requires the coordinated action of host and viral transcription factors, most critically the viral transactivator Tat and the host nuclear factor κB (NF-κB). This activity is disrupted in infected cells that are cultured with extracellular vesicles (EVs) present in human semen, suggesting that they contain factors that could inform the development of new therapeutics. Here, we explored the contents of semen-derived EVs (SEVs) from uninfected donors and individuals with HIV-1 and identified host proteins that interacted with HIV Tat and the NF-κB subunit p65. Integrative network and pathway enrichment analyses of these complexes revealed associations with an array of biological functions regulating gene expression. Several proteins in SEVs bound to both Tat and NF-κB p65: the scaffolding and cell signaling regulatory protein AKAP9, the G protein signaling regulator ARHGEF28, the epigenetic reader BRD2, the small nuclear RNA processor INTS1, and the transcription elongation inhibitor NELFB. When complexed with p65, NELFB also interacted with HEXIM1, another transcription elongation inhibitor, suggesting that SEVs may inhibit HIV-1 propagation through multiple networks of transcriptional activation and repression. Exploring these data and the underlying mechanisms may inform the development of more effective or more durable therapeutics against HIV.
{"title":"Identification of proteins in semen-derived extracellular vesicles that bind to Tat and NF-κB and that may impair HIV replication","authors":"Bryson C. Okeoma, Hussein Kaddour, Wasifa Naushad, Victor Paromov, Ashok Chaudhary, Alessio Noghero, Jack T. Stapleton, Chioma M. Okeoma","doi":"10.1126/scisignal.ado9243","DOIUrl":"10.1126/scisignal.ado9243","url":null,"abstract":"<div >Replication of HIV-1 requires the coordinated action of host and viral transcription factors, most critically the viral transactivator Tat and the host nuclear factor κB (NF-κB). This activity is disrupted in infected cells that are cultured with extracellular vesicles (EVs) present in human semen, suggesting that they contain factors that could inform the development of new therapeutics. Here, we explored the contents of semen-derived EVs (SEVs) from uninfected donors and individuals with HIV-1 and identified host proteins that interacted with HIV Tat and the NF-κB subunit p65. Integrative network and pathway enrichment analyses of these complexes revealed associations with an array of biological functions regulating gene expression. Several proteins in SEVs bound to both Tat and NF-κB p65: the scaffolding and cell signaling regulatory protein AKAP9, the G protein signaling regulator ARHGEF28, the epigenetic reader BRD2, the small nuclear RNA processor INTS1, and the transcription elongation inhibitor NELFB. When complexed with p65, NELFB also interacted with HEXIM1, another transcription elongation inhibitor, suggesting that SEVs may inhibit HIV-1 propagation through multiple networks of transcriptional activation and repression. Exploring these data and the underlying mechanisms may inform the development of more effective or more durable therapeutics against HIV.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 903","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022416","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 : 2025-09-09DOI: 10.1126/scisignal.adx7729
Samuel J. Mabry, Xixi Cao, Yanqi Zhu, Caleb Rowe, Shalin Patel, Camila González-Arancibia, Tiziana Romanazzi, David P. Saleeby, Anna Elam, Hui-Ting Lee, Serhat Turkmen, Shelby N. Lauzon, Cesar E. Hernandez, HaoSheng Sun, Hui Wu, Angela M. Carter, Aurelio Galli
Amphetamines are psychostimulants that are commonly used to treat neuropsychiatric disorders and are prone to misuse. The pathogenesis of amphetamine use disorder (AUD) is associated with dysbiosis (an imbalance in the body’s microbiome) and bacterially produced short-chain fatty acids (SCFAs), which are implicated in the gut-brain axis. Amphetamine exposure in both rats and humans increases the amount of intestinal Fusobacterium nucleatum, which releases SFCAs. Here, we found that colonization of gnotobiotic Drosophila melanogaster with F. nucleatum or supplementing the flies’ diet with the SCFA butyrate enhanced the psychomotor and reward properties of amphetamine. Butyrate inhibits histone deacetylases (HDACs), and knockdown of HDAC1 recapitulated the effects induced by F. nucleatum or butyrate. The enhancement in amphetamine-induced behaviors was mediated by an increase in the amount of released dopamine that resulted from amphetamine-induced reversal of dopamine transporter (DAT) function, termed nonvesicular dopamine release (NVDR). The magnitude of amphetamine-induced NVDR was partially mediated by an increase in DAT abundance stimulated at a transcriptional level, and the administration of F. nucleatum or butyrate enhanced NVDR by increasing DAT expression. The findings indicate that F. nucleatum supports AUD through epigenetic regulation of dopamine signaling and identify potential targets for AUD treatment.
{"title":"Fusobacterium nucleatum enhances amphetamine-induced behavioral responses through a butyrate-driven epigenetic mechanism","authors":"Samuel J. Mabry, Xixi Cao, Yanqi Zhu, Caleb Rowe, Shalin Patel, Camila González-Arancibia, Tiziana Romanazzi, David P. Saleeby, Anna Elam, Hui-Ting Lee, Serhat Turkmen, Shelby N. Lauzon, Cesar E. Hernandez, HaoSheng Sun, Hui Wu, Angela M. Carter, Aurelio Galli","doi":"10.1126/scisignal.adx7729","DOIUrl":"10.1126/scisignal.adx7729","url":null,"abstract":"<div >Amphetamines are psychostimulants that are commonly used to treat neuropsychiatric disorders and are prone to misuse. The pathogenesis of amphetamine use disorder (AUD) is associated with dysbiosis (an imbalance in the body’s microbiome) and bacterially produced short-chain fatty acids (SCFAs), which are implicated in the gut-brain axis. Amphetamine exposure in both rats and humans increases the amount of intestinal <i>Fusobacterium nucleatum</i>, which releases SFCAs. Here, we found that colonization of gnotobiotic <i>Drosophila melanogaster</i> with <i>F. nucleatum</i> or supplementing the flies’ diet with the SCFA butyrate enhanced the psychomotor and reward properties of amphetamine. Butyrate inhibits histone deacetylases (HDACs), and knockdown of HDAC1 recapitulated the effects induced by <i>F. nucleatum</i> or butyrate. The enhancement in amphetamine-induced behaviors was mediated by an increase in the amount of released dopamine that resulted from amphetamine-induced reversal of dopamine transporter (DAT) function, termed nonvesicular dopamine release (NVDR). The magnitude of amphetamine-induced NVDR was partially mediated by an increase in DAT abundance stimulated at a transcriptional level, and the administration of <i>F. nucleatum</i> or butyrate enhanced NVDR by increasing DAT expression. The findings indicate that <i>F. nucleatum</i> supports AUD through epigenetic regulation of dopamine signaling and identify potential targets for AUD treatment.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 903","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022414","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 : 2025-09-02DOI: 10.1126/scisignal.adw3231
Varuna Nangia, Humza Ashraf, Nasreen Marikar, Victor J. Passanisi, Christopher R. Ill, Sabrina L. Spencer
In BRAF-mutant melanoma cells treated with inhibitors of the kinases BRAF and MEK, a subset of cells rapidly and nongenetically adapts to escape drug-induced quiescence and reenters the cell cycle. Here, we investigated the mechanisms enabling this drug escape by computationally reconstructing single-cell lineages from time-lapse imaging data, linking dynamic signaling pathways to distinct cell-cycle fate outcomes. We found that reactivation of the MEK substrate ERK was necessary but not sufficient to drive escape; rather, the activity of the protein complex mTORC1 was also required to promote cell growth and protein synthesis in drug-treated cells destined for cell-cycle reentry. ERK and mTORC1 signaling converged to increase the abundance of cyclin D1 protein, a critical bottleneck for cell-cycle commitment under drug pressure. In cells in which endogenous cyclin D1 was fluorescently tagged using CRISPR, the subset that escaped drug treatment exhibited marked accumulation of cyclin D1 at least 15 hours before cell-cycle reentry, enabling early prediction of future drug escape. Cyclin D1 thus represents both an early biomarker and potential therapeutic target for suppressing drug escape in melanoma. We observed a similar mTORC1-driven mechanism underlying escape in lung cancer cells, but not colon cancer cells, highlighting partial generalizability across cancer types.
{"title":"MAPK and mTORC1 signaling converge to drive cyclin D1 protein production to enable cell cycle reentry in melanoma persister cells","authors":"Varuna Nangia, Humza Ashraf, Nasreen Marikar, Victor J. Passanisi, Christopher R. Ill, Sabrina L. Spencer","doi":"10.1126/scisignal.adw3231","DOIUrl":"10.1126/scisignal.adw3231","url":null,"abstract":"<div >In <i>BRAF</i>-mutant melanoma cells treated with inhibitors of the kinases BRAF and MEK, a subset of cells rapidly and nongenetically adapts to escape drug-induced quiescence and reenters the cell cycle. Here, we investigated the mechanisms enabling this drug escape by computationally reconstructing single-cell lineages from time-lapse imaging data, linking dynamic signaling pathways to distinct cell-cycle fate outcomes. We found that reactivation of the MEK substrate ERK was necessary but not sufficient to drive escape; rather, the activity of the protein complex mTORC1 was also required to promote cell growth and protein synthesis in drug-treated cells destined for cell-cycle reentry. ERK and mTORC1 signaling converged to increase the abundance of cyclin D1 protein, a critical bottleneck for cell-cycle commitment under drug pressure. In cells in which endogenous cyclin D1 was fluorescently tagged using CRISPR, the subset that escaped drug treatment exhibited marked accumulation of cyclin D1 at least 15 hours before cell-cycle reentry, enabling early prediction of future drug escape. Cyclin D1 thus represents both an early biomarker and potential therapeutic target for suppressing drug escape in melanoma. We observed a similar mTORC1-driven mechanism underlying escape in lung cancer cells, but not colon cancer cells, highlighting partial generalizability across cancer types.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 902","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935559","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 : 2025-09-02DOI: 10.1126/scisignal.adu8839
Daozhong Jin, Hong Chen, Meng-Hua Zhou, Yuying Huang, Shao-Rui Chen, Hui-Lin Pan
Opioids relieve pain by activating μ-opioid receptors (MORs), which inhibit communication between pain-sensing neurons (nociceptors) and the spinal cord. However, prolonged opioid use can paradoxically lead to increased pain sensitivity (hyperalgesia) and reduced analgesic efficacy (tolerance), partly because of the activation of NMDA-type glutamate receptors (NMDARs) at the central terminals of primary sensory neurons in the spinal cord. Here, we identified a critical role for the G protein Gαq in this paradox. Pharmacological inhibition of Gαq in rats reversed morphine-induced increases in NMDAR phosphorylation, synaptic trafficking, and activity at sensory neuron terminals and reduced morphine-induced excitatory nociceptive input to spinal dorsal horn neurons. Morphine enhanced Gαq coupling specifically to metabotropic glutamate receptor 5 (mGluR5) dimers in the spinal cord. Furthermore, targeted knockdown of Gαq in dorsal root ganglion neurons in mice normalized NMDAR-related changes and prevented NMDAR-mediated synaptic potentiation triggered by MOR activation. In addition, either pharmacological or genetic disruption of Gαq signaling enhanced morphine’s analgesic effects while reducing hyperalgesia and tolerance. These findings reveal that Gαq signaling contributes to opioid-induced NMDAR hyperactivity at nociceptor central terminals by promoting MOR-mGluR5 cross-talk. Targeting this pathway may improve the safety and efficacy of opioid-based pain management.
{"title":"Gαq signaling in primary sensory neurons shifts opioid analgesia to NMDA receptor–driven tolerance and hyperalgesia","authors":"Daozhong Jin, Hong Chen, Meng-Hua Zhou, Yuying Huang, Shao-Rui Chen, Hui-Lin Pan","doi":"10.1126/scisignal.adu8839","DOIUrl":"10.1126/scisignal.adu8839","url":null,"abstract":"<div >Opioids relieve pain by activating μ-opioid receptors (MORs), which inhibit communication between pain-sensing neurons (nociceptors) and the spinal cord. However, prolonged opioid use can paradoxically lead to increased pain sensitivity (hyperalgesia) and reduced analgesic efficacy (tolerance), partly because of the activation of NMDA-type glutamate receptors (NMDARs) at the central terminals of primary sensory neurons in the spinal cord. Here, we identified a critical role for the G protein Gα<sub>q</sub> in this paradox. Pharmacological inhibition of Gα<sub>q</sub> in rats reversed morphine-induced increases in NMDAR phosphorylation, synaptic trafficking, and activity at sensory neuron terminals and reduced morphine-induced excitatory nociceptive input to spinal dorsal horn neurons. Morphine enhanced Gα<sub>q</sub> coupling specifically to metabotropic glutamate receptor 5 (mGluR5) dimers in the spinal cord. Furthermore, targeted knockdown of Gα<sub>q</sub> in dorsal root ganglion neurons in mice normalized NMDAR-related changes and prevented NMDAR-mediated synaptic potentiation triggered by MOR activation. In addition, either pharmacological or genetic disruption of Gα<sub>q</sub> signaling enhanced morphine’s analgesic effects while reducing hyperalgesia and tolerance. These findings reveal that Gα<sub>q</sub> signaling contributes to opioid-induced NMDAR hyperactivity at nociceptor central terminals by promoting MOR-mGluR5 cross-talk. Targeting this pathway may improve the safety and efficacy of opioid-based pain management.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 902","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adu8839","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144935537","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 : 2025-08-26DOI: 10.1126/scisignal.aeb6175
Annalisa M. VanHook
Estrogen protects against kidney injury through both genomic and nongenomic mechanisms.
雌激素通过基因组和非基因组机制保护肾脏免受损伤。
{"title":"Estrogen-powered kidney protection","authors":"Annalisa M. VanHook","doi":"10.1126/scisignal.aeb6175","DOIUrl":"10.1126/scisignal.aeb6175","url":null,"abstract":"<div >Estrogen protects against kidney injury through both genomic and nongenomic mechanisms.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 901","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144905652","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}
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