Science Signaling最新文献_第3页

Estrogen-powered kidney protection 雌激素驱动的肾脏保护

IF 6.6 1区生物学

Science Signaling Pub Date : 2025-08-26 DOI: 10.1126/scisignal.aeb6175

Annalisa M. VanHook

引用次数: 0

Analysis of stress-induced small proteins in Escherichia coli reveals that YoaI mediates cross-talk between distinct signaling systems 对大肠杆菌中应激诱导的小蛋白的分析表明，YoaI介导不同信号系统之间的串扰

IF 6.6 1区生物学

Science Signaling Pub Date : 2025-08-26 DOI: 10.1126/scisignal.adu7253

Sangeevan Vellappan, Junhong Sun, John Favate, Pranavi Jagadeesan, Debbie Cerda, Premal Shah, Srujana S. Yadavalli

{"title":"Analysis of stress-induced small proteins in Escherichia coli reveals that YoaI mediates cross-talk between distinct signaling systems","authors":"Sangeevan Vellappan, Junhong Sun, John Favate, Pranavi Jagadeesan, Debbie Cerda, Premal Shah, Srujana S. Yadavalli","doi":"10.1126/scisignal.adu7253","DOIUrl":"10.1126/scisignal.adu7253","url":null,"abstract":"<div >Bacterial small proteins (≤50 amino acids) are an emerging class of regulators that modulate the activity of signaling networks that enable bacterial adaptation to stress. The <i>Escherichia coli</i> genome encodes at least 150 small proteins, most of which are functionally uncharacterized. We identified and characterized 17 small proteins induced in <i>E</i>. <i>coli</i> during magnesium (Mg<sup>2+</sup>) starvation using ribosome profiling, RNA sequencing, and transcriptional reporter assays. Several of these were transcriptionally activated by the PhoQ-PhoP two-component signaling system, which is crucial for Mg<sup>2+</sup> homeostasis. Deletion or overexpression of some of these small proteins led to growth defects and changes in cell size under low-Mg<sup>2+</sup> conditions, indicating physiological roles in stress adaptation. The small transmembrane protein YoaI, which was transcriptionally induced by the phosphate-responsive PhoR-PhoB signaling pathway, increased in abundance under Mg<sup>2+</sup> limitation independently of <i>yoaI</i> transcription or PhoQ-PhoP signaling. YoaI activated a third signaling system, EnvZ-OmpR, which mediates responses to osmotic stress. Overall, this study establishes an initial framework for understanding how small proteins contribute to bacterial stress adaptation by facilitating cross-talk between different signaling systems. Our results suggest that these proteins play broader roles in coordinating stress responses, reflecting the interconnected nature of cellular stress networks rather than strictly compartmentalized pathways responding to specific stressors.</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":"144905651","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}

引用次数: 0

Amylin receptor subunit interactions are modulated by agonists and determine signaling 胰淀素受体亚单位相互作用由激动剂调节并决定信号传导

IF 6.6 1区生物学

Science Signaling Pub Date : 2025-08-19 DOI: 10.1126/scisignal.adt8127

Sandra E. Gostynska, Jordan A. Karim, Bailee E. Ford, Peyton H. Gordon, Katie M. Babin, Asuka Inoue, Nevin A. Lambert, Augen A. Pioszak

{"title":"Amylin receptor subunit interactions are modulated by agonists and determine signaling","authors":"Sandra E. Gostynska, Jordan A. Karim, Bailee E. Ford, Peyton H. Gordon, Katie M. Babin, Asuka Inoue, Nevin A. Lambert, Augen A. Pioszak","doi":"10.1126/scisignal.adt8127","DOIUrl":"10.1126/scisignal.adt8127","url":null,"abstract":"<div >Three amylin receptors (AMYRs) mediate the metabolic actions of the peptide hormone amylin and are drug targets for diabetes and obesity. AMY<sub>1</sub>R, AMY<sub>2</sub>R, and AMY<sub>3</sub>R are heterodimers consisting of the calcitonin receptor (CTR), a G protein–coupled receptor, paired with a RAMP1, RAMP2, or RAMP3 accessory subunit, respectively, which increases amylin potency. Here, we found that the AMYRs had distinct basal subunit equilibria that were modulated by peptide agonists and determined the extent of cAMP signaling downstream of receptor activation. By developing a biochemical assay that resolves the AMYR heterodimers and free subunits, we found that the AMY<sub>1</sub>R and AMY<sub>2</sub>R subunit distributions favored free CTR and RAMPs and that rat amylin promoted association of the constituent subunits of AMY<sub>1</sub>R and AMY<sub>2</sub>R. The agonist αCGRP also induced AMY<sub>1</sub>R subunit association. A stronger interaction between the CTR and the RAMP3 transmembrane domains yielded a more stable AMY<sub>3</sub>R, and human and salmon calcitonin agonists promoted AMY<sub>3</sub>R dissociation. Similar changes in subunit association and dissociation were observed in live-cell membranes, and G protein coupling and cAMP signaling assays showed how these changes altered signaling. Our findings have implications for AMYR biology and drug development and reveal regulation of heteromeric GPCR signaling through subunit interaction dynamics.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 900","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144870112","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}

引用次数: 0

Hox-C12 coordinates β2-adrenoceptor coupling to a cAMP/calcium feedforward loop to drive invasion in triple-negative breast cancer cox - c12协调β2-肾上腺素受体偶联至cAMP/钙前馈回路，驱动三阴性乳腺癌的侵袭

IF 6.6 1区生物学

Science Signaling Pub Date : 2025-08-19 DOI: 10.1126/scisignal.adq8279

Terrance Lam, Bailey Cardwell, Bonan Liu, Cheng Peng, Mia Spark, Sandra Sursock, Cameron J. Nowell, Andrew M. Ellisdon, Aeson Chang, Alastair C. Keen, Erica K. Sloan, Michelle L. Halls

{"title":"Hox-C12 coordinates β2-adrenoceptor coupling to a cAMP/calcium feedforward loop to drive invasion in triple-negative breast cancer","authors":"Terrance Lam, Bailey Cardwell, Bonan Liu, Cheng Peng, Mia Spark, Sandra Sursock, Cameron J. Nowell, Andrew M. Ellisdon, Aeson Chang, Alastair C. Keen, Erica K. Sloan, Michelle L. Halls","doi":"10.1126/scisignal.adq8279","DOIUrl":"10.1126/scisignal.adq8279","url":null,"abstract":"<div >Noradrenaline released from sympathetic neurons accelerates cancer metastasis by activating β<sub>2</sub>-adrenergic receptors (β<sub>2</sub>-adrenoceptors) on tumor cells to promote invasion. We previously showed that the β<sub>2</sub>-adrenoceptor promotes invasive behavior in a metastatic triple-negative breast cancer (TNBC) cell line by activating a cAMP- and calcium-mediated feedforward loop. Here, we found this mechanism in most TNBC lines that have an active β<sub>2</sub>-adrenoceptor. Integrated analysis of transcriptomic datasets revealed <i>HOXC12</i>, which encodes a developmental homeobox transcription factor, as the most discriminating gene separating cell lines with the feedforward loop and those without it. The high expression of <i>HOXC12</i> did not correlate with transcriptional changes in integral proteins associated with cAMP or calcium signaling, and immunostaining showed cytosolic localization of Hox-C12, suggesting that it played a nontranscriptional role. Knocking out <i>HOXC12</i> prevented β<sub>2</sub>-adrenoceptor–mediated calcium signaling and invasion in cultured TNBC cells. In basal breast cancers, <i>HOXC12</i> expression in tumors negatively correlated with overall and disease-free survival in patients. These findings identify a key mediator, Hox-C12, in the coordination of invasion driven by cAMP and calcium signaling in β<sub>2</sub>-adrenoceptor–responsive TNBC cells.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 900","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adq8279","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144870111","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}

引用次数: 0

Tailored receptor modulators 定制受体调节剂

IF 6.6 1区生物学

Science Signaling Pub Date : 2025-08-12 DOI: 10.1126/scisignal.aeb2685

John F. Foley

引用次数: 0

The kinase ERK plays a conserved dominant role in the heterogeneity of epithelial-mesenchymal transition in pancreatic cancer cells ERK激酶在胰腺癌细胞上皮-间质转化的异质性中起保守的主导作用

IF 6.6 1区生物学

Science Signaling Pub Date : 2025-08-12 DOI: 10.1126/scisignal.ads7002

Michelle C. Barbeau, Brooke A. Brown, Sara J. Adair, Todd W. Bauer, Matthew J. Lazzara

{"title":"The kinase ERK plays a conserved dominant role in the heterogeneity of epithelial-mesenchymal transition in pancreatic cancer cells","authors":"Michelle C. Barbeau, Brooke A. Brown, Sara J. Adair, Todd W. Bauer, Matthew J. Lazzara","doi":"10.1126/scisignal.ads7002","DOIUrl":"10.1126/scisignal.ads7002","url":null,"abstract":"<div >Epithelial-mesenchymal transition (EMT) occurs heterogeneously among carcinoma cells to promote chemoresistance. Identifying the signaling pathways involved will nominate drug combinations to promote chemoresponse, but cell population–level studies can be misleading, and single-cell transcriptomics are limited to indirect ontology-based inferences. To understand EMT heterogeneity at a signaling protein level, we combined iterative indirect immunofluorescence imaging of pancreas cancer cells and tumors and mutual information (MI) analysis. Focusing first on mitogen-activated protein kinase pathways, MI indicated that cell-to-cell variation in ERK activity determined EMT heterogeneity in response to different growth factors and chemotherapeutics but that JNK compensated when MEK was inhibited. Population-level models could not capture these experimentally validated MI inferences. The dominant role of ERK was consistently indicated by MI even when the analysis was expanded to include seven potential EMT-regulating signaling nodes. More generally, this work provides an approach for studying multivariate signaling-phenotype relationships based on protein measurements in any setting.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 899","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833411","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}

引用次数: 0

The lncRNA EPIC1 suppresses dsRNA-induced type I IFN signaling and is a therapeutic target to enhance TNBC response to PD-1 inhibition lncRNA EPIC1抑制dsrna诱导的I型IFN信号，是增强TNBC对PD-1抑制反应的治疗靶点

IF 6.6 1区生物学

Science Signaling Pub Date : 2025-08-12 DOI: 10.1126/scisignal.adr9131

Dhamotharan Pattarayan, Yue Wang, Zehua Wang, Sihan Li, Xiaofei Wang, Yuang Chen, Yifei Wang, Chien-Yu Chen, Avishek Bhuniya, Ghanshyam Singh Yadav, Wen Xie, Udai S. Kammula, Song Li, Min Zhang, Da Yang

{"title":"The lncRNA EPIC1 suppresses dsRNA-induced type I IFN signaling and is a therapeutic target to enhance TNBC response to PD-1 inhibition","authors":"Dhamotharan Pattarayan, Yue Wang, Zehua Wang, Sihan Li, Xiaofei Wang, Yuang Chen, Yifei Wang, Chien-Yu Chen, Avishek Bhuniya, Ghanshyam Singh Yadav, Wen Xie, Udai S. Kammula, Song Li, Min Zhang, Da Yang","doi":"10.1126/scisignal.adr9131","DOIUrl":"10.1126/scisignal.adr9131","url":null,"abstract":"<div >Increases in retroelement-derived double-stranded RNAs (dsRNAs) in various types of cancer cells facilitate the activation of antitumor immune responses. The long noncoding RNA EPIC1 interacts with the histone methyltransferase EZH2 and contributes to tumor immune evasion. Here, we found that EPIC1 in tumor cells suppressed cytoplasmic dsRNA accumulation, type I interferon (IFN) responses, and antitumor immunity. In various cancer cell lines, knockdown of EPIC1 stimulated the production of dsRNA from retroelements and an antiviral-like type I IFN response that activated immune cells. EPIC1 inhibited the expression of LINE, SINE, and LTR retroelements that were also repressed by EZH2, suggesting a potential role for the EPIC1-EZH2 interaction in regulating dsRNA production. In a humanized mouse model, in vivo delivery of EPIC1-targeting oligonucleotides enhanced dsRNA accumulation in breast cancer xenografts, reduced tumor growth, and increased the infiltration of T cells and inflammatory macrophages into tumors. Furthermore, EPIC1 knockdown improved the therapeutic efficacy of the immunotherapy drug pembrolizumab, a PD-1 inhibitor, in the humanized mouse model. Together, our findings establish EPIC1 as a key regulator of dsRNA-mediated type I IFN responses and highlight its potential as a therapeutic target to improve the efficacy of immunotherapy.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 899","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833412","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}

引用次数: 0

Tumor-infiltrating nociceptor neurons promote immunosuppression 肿瘤浸润性伤害感受器神经元促进免疫抑制

IF 6.6 1区生物学

Science Signaling Pub Date : 2025-08-05 DOI: 10.1126/scisignal.ads7889

Anthony C. Restaino, Maryam Ahmadi, Tuany Eichwald, Amin Reza Nikpoor, Austin Walz, Mohammad Balood, Sebastien Talbot, Paola D. Vermeer

{"title":"Tumor-infiltrating nociceptor neurons promote immunosuppression","authors":"Anthony C. Restaino, Maryam Ahmadi, Tuany Eichwald, Amin Reza Nikpoor, Austin Walz, Mohammad Balood, Sebastien Talbot, Paola D. Vermeer","doi":"10.1126/scisignal.ads7889","DOIUrl":"10.1126/scisignal.ads7889","url":null,"abstract":"<div >Small extracellular vesicles (sEVs) released from tumors recruit nociceptor neurons to the tumor bed. Here, we found that ablating these neurons in mouse models of head and neck carcinoma and melanoma reduced the infiltration of myeloid-derived suppressor cells (MDSCs). Moreover, sEV-deficient tumors failed to develop in mice lacking nociceptor neurons. We investigated the interplay between tumor-infiltrating nociceptors and immune cells in head and neck squamous cell carcinoma (HNSCC) and melanoma. Upon exposure to cancer-derived sEVs, mouse dorsal root ganglion (DRG) neurons secreted increased amounts of substance P, IL-6, and injury-associated neuronal markers. Patient-derived sEVs sensitized DRG neurons to capsaicin, implying enhanced nociceptor responsiveness. Furthermore, nociceptors cultured with sEVs induced an immunosuppressed state in CD8<sup>+</sup> T cells. Incubation with conditioned medium from cocultures of neurons and cancer cells resulted in increased expression of markers of MDSCs and suppressive function in primary bone marrow cells, and the combination of neuron-conditioned medium and cancer sEVs promoted checkpoint receptor expression on T cells. Together, these findings reveal that nociceptor neurons facilitate CD8<sup>+</sup> T cell exhaustion and bolster MDSC infiltration into HNSCC and melanoma. Consequently, targeting nociceptors may provide a strategy to disrupt detrimental neuroimmune cross-talk in cancer and potentiate antitumor immunity.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 898","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.ads7889","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144782960","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}

引用次数: 0

Tumor-derived small extracellular vesicles reprogram sensory nerves to drive immunosuppression in the tumor microenvironment 肿瘤来源的小细胞外囊泡重编程感觉神经以驱动肿瘤微环境中的免疫抑制

IF 6.6 1区生物学

Science Signaling Pub Date : 2025-08-05 DOI: 10.1126/scisignal.ady6769

Leah Boyd, Jeremy C. Borniger

引用次数: 0

USP5 deubiquitylates and stabilizes FcεRIγ to enhance IgE-induced mast cell activation and allergic inflammation USP5去泛素化并稳定FcεRIγ以增强ige诱导的肥大细胞活化和过敏性炎症

IF 6.6 1区生物学

Science Signaling Pub Date : 2025-07-29 DOI: 10.1126/scisignal.adr3411

Zi-Wen Zhou, Xue-Ting Xu, Qiu-Ni Liang, Yan-Mei Zhou, Wan-Zhen Hu, Shan Liu, Yu-Xin Jiao, Shu-Chen Zhang, Kunmei Ji, Jia-Jie Chen

{"title":"USP5 deubiquitylates and stabilizes FcεRIγ to enhance IgE-induced mast cell activation and allergic inflammation","authors":"Zi-Wen Zhou, Xue-Ting Xu, Qiu-Ni Liang, Yan-Mei Zhou, Wan-Zhen Hu, Shan Liu, Yu-Xin Jiao, Shu-Chen Zhang, Kunmei Ji, Jia-Jie Chen","doi":"10.1126/scisignal.adr3411","DOIUrl":"10.1126/scisignal.adr3411","url":null,"abstract":"<div >Antigen-mediated aggregation of immunoglobulin E (IgE) bound to the high-affinity IgE receptor (FcεRI) initiates mast cell activation and allergic inflammation. Here, we investigated the role of ubiquitin-specific protease 5 (USP5) in IgE-mediated mast cell activation and its regulation of FcεRIγ stability. We found that USP5 knockdown inhibited the IgE-induced release of β-hexosaminidase and histamine from mast cells and attenuated allergic inflammation in mice. USP5 interacted with FcεRIγ in mast cells, leading to its deubiquitylation and stabilization. In addition, USP5 reversed the K48-linked polyubiquitylation of FcεRIγ. USP5 knockdown in mast cells or HEK293T cells increased the binding of the E3 ubiquitin ligase Cbl-b to FcεRIγ, leading to an increase in FcεRIγ polyubiquitylation and degradation. The USP5 inhibitor WP1130 attenuated IgE-mediated mast cell activation and allergic inflammation in mice. Together, these findings describe the molecular mechanism of USP5-mediated regulation of FcεRIγ stability in mast cells and identify the USP5-FcεRIγ axis as a potential drug target for the therapy of IgE/FcεRI-mediated allergic diseases.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 897","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144725733","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}

引用次数: 0