Science Signaling最新文献_第10页

Plant MDL proteins synergize with the cytokine MIF at CXCR2 and CXCR4 receptors in human cells 在人类细胞中，植物MDL蛋白与细胞因子MIF协同作用于CXCR2和CXCR4受体。

IF 7.3 1区生物学

Science Signaling Pub Date : 2023-11-21 DOI: 10.1126/scisignal.adg2621

Lukas Spiller, Ramu Manjula, Franz Leissing, Jerome Basquin, Priscila Bourilhon, Dzmitry Sinitski, Markus Brandhofer, Sophie Levecque, Simona Gerra, Björn Sabelleck, Lin Zhang, Regina Feederle, Andrew Flatley, Adrian Hoffmann, Ralph Panstruga, Jürgen Bernhagen, Elias Lolis

{"title":"Plant MDL proteins synergize with the cytokine MIF at CXCR2 and CXCR4 receptors in human cells","authors":"Lukas Spiller, Ramu Manjula, Franz Leissing, Jerome Basquin, Priscila Bourilhon, Dzmitry Sinitski, Markus Brandhofer, Sophie Levecque, Simona Gerra, Björn Sabelleck, Lin Zhang, Regina Feederle, Andrew Flatley, Adrian Hoffmann, Ralph Panstruga, Jürgen Bernhagen, Elias Lolis","doi":"10.1126/scisignal.adg2621","DOIUrl":"10.1126/scisignal.adg2621","url":null,"abstract":"<div >Mammalian macrophage migration inhibitory factor (MIF) and its paralog, D-dopachrome tautomerase, are multifunctional inflammatory cytokines. Plants have orthologous MIF and D-dopachrome tautomerase–like (MDL) proteins that mimic some of the effects of MIF on immune cells in vitro. We explored the structural and functional similarities between the three Arabidopsis thaliana MDLs and MIF. X-ray crystallography of the MDLs revealed high structural similarity between MDL and MIF homotrimers and suggested a potential explanation for the lack of tautomerase activity in the MDLs. MDL1 and MDL2 interacted with each other and with MIF in vitro, in yeast, and in plant leaves and formed hetero-oligomeric complexes with MIF in vitro. The MDLs stimulated signaling through the MIF receptors CXCR2 or CXCR4 and enhanced the responses to MIF in a yeast reporter system, in human neutrophils, and in human lung epithelial cells. Pharmacological inhibitors that disrupted MIF activity or prevented the formation of MIF-MDL hetero-oligomers blocked the observed synergism. These findings demonstrate that MDLs can enhance cellular responses to MIF, which may have functional implications in tissues exposed to MDLs from the diet or environment.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2023-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138292246","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

Enteric glia promote visceral hypersensitivity during inflammation through intercellular signaling with gut nociceptors 肠胶质细胞通过与肠道伤害感受器的细胞间信号传导促进炎症期间内脏的超敏反应。

IF 7.3 1区生物学

Science Signaling Pub Date : 2023-11-21 DOI: 10.1126/scisignal.adg1668

Wilmarie Morales-Soto, Jacques Gonzales, William F. Jackson, Brian D. Gulbransen

{"title":"Enteric glia promote visceral hypersensitivity during inflammation through intercellular signaling with gut nociceptors","authors":"Wilmarie Morales-Soto, Jacques Gonzales, William F. Jackson, Brian D. Gulbransen","doi":"10.1126/scisignal.adg1668","DOIUrl":"10.1126/scisignal.adg1668","url":null,"abstract":"<div >Inflammation in the intestines causes abdominal pain that is challenging to manage. The terminals of sensory neurons innervating the gut are surrounded by glia. Here, using a mouse model of acute colitis, we found that enteric glia contribute to visceral pain by secreting factors that sensitized sensory nerves innervating the gut in response to inflammation. Acute colitis induced a transient increase in the production of proinflammatory cytokines in the intestines of male and female mice. Of these, IL-1β was produced in part by glia and augmented the opening of the intercellular communication hemichannel connexin-43 in glia, which made normally innocuous stimuli painful in female mice. Chemogenetic glial activation paired with calcium imaging in nerve terminals demonstrated that glia sensitized gut-innervating nociceptors only under inflammatory conditions. This inflammatory, glial-driven visceral hypersensitivity involved an increased abundance of the enzyme COX-2 in glia, resulting in greater production and release of prostaglandin E2 that activated EP4 receptors on sensory nerve terminals. Blocking EP4 receptors reduced nociceptor sensitivity in response to glial stimulation in tissue samples from colitis-model mice, and impairing glial connexin-43 reduced visceral hypersensitivity induced by IL-1β in female mice. The findings suggest that therapies targeting enteric glial–neuron signaling might alleviate visceral pain caused by inflammatory disorders.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2023-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138292245","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

Beige is the color of keeping weight off 米色是减肥的颜色。

IF 7.3 1区生物学

Science Signaling Pub Date : 2023-11-21 DOI: 10.1126/scisignal.adm9735

Wei Wong

引用次数: 0

The TMEM16A anion channel as a versatile regulator of vascular tone TMEM16A阴离子通道作为血管张力的多功能调节剂。

IF 7.3 1区生物学

Science Signaling Pub Date : 2023-11-14 DOI: 10.1126/scisignal.adk5661

Paolo Tammaro

引用次数: 0

Proinflammatory apoptosis 炎性细胞凋亡。

IF 7.3 1区生物学

Science Signaling Pub Date : 2023-11-14 DOI: 10.1126/scisignal.adm8181

Annalisa M. VanHook

引用次数: 0

Impaired intracellular Ca2+ signaling contributes to age-related cerebral small vessel disease in Col4a1 mutant mice 受损的细胞内Ca2+信号有助于Col4a1突变小鼠年龄相关的脑血管疾病。

IF 7.3 1区生物学

Science Signaling Pub Date : 2023-11-14 DOI: 10.1126/scisignal.adi3966

Evan Yamasaki, Pratish Thakore, Sher Ali, Alfredo Sanchez Solano, Xiaowei Wang, Xiao Gao, Cassandre Labelle-Dumais, Myriam M. Chaumeil, Douglas B. Gould, Scott Earley

{"title":"Impaired intracellular Ca2+ signaling contributes to age-related cerebral small vessel disease in Col4a1 mutant mice","authors":"Evan Yamasaki, Pratish Thakore, Sher Ali, Alfredo Sanchez Solano, Xiaowei Wang, Xiao Gao, Cassandre Labelle-Dumais, Myriam M. Chaumeil, Douglas B. Gould, Scott Earley","doi":"10.1126/scisignal.adi3966","DOIUrl":"10.1126/scisignal.adi3966","url":null,"abstract":"<div >Humans and mice with mutations in COL4A1 and COL4A2 manifest hallmarks of cerebral small vessel disease (cSVD). Mice with a missense mutation in Col4a1 at amino acid 1344 (Col4a1+/G1344D) exhibit age-dependent intracerebral hemorrhages (ICHs) and brain lesions. Here, we report that this pathology was associated with the loss of myogenic vasoconstriction, an intrinsic vascular response essential for the autoregulation of cerebral blood flow. Electrophysiological analyses showed that the loss of myogenic constriction resulted from blunted pressure-induced smooth muscle cell (SMC) membrane depolarization. Furthermore, we found that dysregulation of membrane potential was associated with impaired Ca2+-dependent activation of large-conductance Ca2+-activated K+ (BK) and transient receptor potential melastatin 4 (TRPM4) cation channels linked to disruptions in sarcoplasmic reticulum (SR) Ca2+ signaling. Col4a1 mutations impair protein folding, which can cause SR stress. Treating Col4a1+/G1344D mice with 4-phenylbutyrate, a compound that promotes the trafficking of misfolded proteins and alleviates SR stress, restored SR Ca2+ signaling, maintained BK and TRPM4 channel activity, prevented loss of myogenic tone, and reduced ICHs. We conclude that alterations in SR Ca2+ handling that impair ion channel activity result in dysregulation of SMC membrane potential and loss of myogenic tone and contribute to age-related cSVD in Col4a1+/G1344D mice.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"107592638","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

Vasodilators activate the anion channel TMEM16A in endothelial cells to reduce blood pressure 血管扩张剂激活内皮细胞中的阴离子通道TMEM16A以降低血压。

IF 7.3 1区生物学

Science Signaling Pub Date : 2023-11-14 DOI: 10.1126/scisignal.adh9399

Alejandro Mata-Daboin, Tessa A. C. Garrud, Carlos Fernandez-Pena, Dieniffer Peixoto-Neves, M. Dennis Leo, Angelica K. Bernardelli, Purnima Singh, Kafait U. Malik, Jonathan H. Jaggar

{"title":"Vasodilators activate the anion channel TMEM16A in endothelial cells to reduce blood pressure","authors":"Alejandro Mata-Daboin, Tessa A. C. Garrud, Carlos Fernandez-Pena, Dieniffer Peixoto-Neves, M. Dennis Leo, Angelica K. Bernardelli, Purnima Singh, Kafait U. Malik, Jonathan H. Jaggar","doi":"10.1126/scisignal.adh9399","DOIUrl":"10.1126/scisignal.adh9399","url":null,"abstract":"<div >Systemic blood pressure is acutely controlled by total peripheral resistance as determined by the diameter of small arteries and arterioles, the contractility of which is regulated by endothelial cells lining the lumen of blood vessels. We investigated the physiological functions of the chloride (Cl−) channel TMEM16A in endothelial cells. TMEM16A channels generated calcium (Ca2+)–activated Cl− currents in endothelial cells from control (TMEM16Afl/fl) mice that were absent in those from mice with tamoxifen-inducible, endothelial cell–specific knockout of TMEM16A (TMEM16A ecKO). TMEM16A currents in endothelial cells were activated by the muscarinic receptor agonist acetylcholine and an agonist of the Ca2+ channel TRPV4, which localized in nanoscale proximity with TMEM16A as assessed by single-molecule localization imaging of endothelial cells. Acetylcholine stimulated TMEM16A currents by activating Ca2+ influx through surface TRPV4 channels without altering the nanoscale properties of TMEM16A and TRPV4 surface clusters or their colocalization. In pressurized arteries, activation of TMEM16A channels in endothelial cells induced by acetylcholine; TRPV4 channel stimulation; or intraluminal ATP, another vasodilator, produced hyperpolarization and dilation. Furthermore, deficiency of TMEM16A channels in endothelial cells resulted in increased systemic blood pressure in conscious mice. These data indicate that vasodilators stimulate TRPV4 channels, leading to Ca2+-dependent activation of nearby TMEM16A channels in endothelial cells to produce arterial hyperpolarization, vasodilation, and reduced blood pressure. Thus, TMEM16A is an anion channel in endothelial cells that regulates arterial contractility and blood pressure.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10694922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"107592641","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

Axon, “axoff” Axon，axoff。

IF 7.3 1区生物学

Science Signaling Pub Date : 2023-11-07 DOI: 10.1126/scisignal.adm7040

Amy E. Baek

引用次数: 0

Chemokines form complex signals during inflammation and disease that can be decoded by extracellular matrix proteoglycans 趋化因子在炎症和疾病期间形成复杂的信号，可以通过细胞外基质蛋白聚糖解码。

IF 7.3 1区生物学

Science Signaling Pub Date : 2023-11-07 DOI: 10.1126/scisignal.adf2537

Amanda J. L. Ridley, Yaqing Ou, Richard Karlsson, Nabina Pun, Holly L. Birchenough, Iashia Z. Mulholland, Mary L. Birch, Andrew S. MacDonald, Thomas A. Jowitt, Craig Lawless, Rebecca L. Miller, Douglas P. Dyer

{"title":"Chemokines form complex signals during inflammation and disease that can be decoded by extracellular matrix proteoglycans","authors":"Amanda J. L. Ridley, Yaqing Ou, Richard Karlsson, Nabina Pun, Holly L. Birchenough, Iashia Z. Mulholland, Mary L. Birch, Andrew S. MacDonald, Thomas A. Jowitt, Craig Lawless, Rebecca L. Miller, Douglas P. Dyer","doi":"10.1126/scisignal.adf2537","DOIUrl":"10.1126/scisignal.adf2537","url":null,"abstract":"<div >Chemokine-driven leukocyte recruitment is a key component of the immune response and of various diseases. Therapeutically targeting the chemokine system in inflammatory disease has been unsuccessful, which has been attributed to redundancy. We investigated why chemokines instead have specific, specialized functions, as demonstrated by multiple studies. We analyzed the expression of genes encoding chemokines and their receptors across species, tissues, and diseases. This analysis revealed complex expression patterns such that genes encoding multiple chemokines that mediated recruitment of the same leukocyte type were expressed in the same context, such as the genes encoding the CXCR3 ligands CXCL9, CXCL10, and CXCL11. Through biophysical approaches, we showed that these chemokines differentially interacted with extracellular matrix glycosaminoglycans (ECM GAGs), which was enhanced by sulfation of specific GAGs. Last, in vivo approaches demonstrated that GAG binding was critical for the CXCL9-dependent recruitment of specific T cell subsets but not of others, irrespective of CXCR3 expression. Our data demonstrate that interactions with ECM GAGs regulated whether chemokines were presented on cell surfaces or remained more soluble, thereby affecting chemokine availability and ensuring specificity of chemokine action. Our findings provide a mechanistic understanding of chemokine-mediated immune cell recruitment and identify strategies to target specific chemokines during inflammatory disease.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2023-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71487963","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

A conserved mechanism for JNK-mediated loss of Notch function in advanced prostate cancer JNK介导的晚期前列腺癌症Notch功能缺失的保守机制。

IF 7.3 1区生物学

Science Signaling Pub Date : 2023-11-07 DOI: 10.1126/scisignal.abo5213

Cheng-Wei Wang, Marie Clémot, Takao Hashimoto, Johnny A. Diaz, Lauren M. Goins, Andrew S. Goldstein, Raghavendra Nagaraj, Utpal Banerjee

{"title":"A conserved mechanism for JNK-mediated loss of Notch function in advanced prostate cancer","authors":"Cheng-Wei Wang, Marie Clémot, Takao Hashimoto, Johnny A. Diaz, Lauren M. Goins, Andrew S. Goldstein, Raghavendra Nagaraj, Utpal Banerjee","doi":"10.1126/scisignal.abo5213","DOIUrl":"10.1126/scisignal.abo5213","url":null,"abstract":"<div >Dysregulated Notch signaling is a common feature of cancer; however, its effects on tumor initiation and progression are highly variable, with Notch having either oncogenic or tumor-suppressive functions in various cancers. To better understand the mechanisms that regulate Notch function in cancer, we studied Notch signaling in a Drosophila tumor model, prostate cancer–derived cell lines, and tissue samples from patients with advanced prostate cancer. We demonstrated that increased activity of the Src-JNK pathway in tumors inactivated Notch signaling because of JNK pathway–mediated inhibition of the expression of the gene encoding the Notch S2 cleavage protease, Kuzbanian, which is critical for Notch activity. Consequently, inactive Notch accumulated in cells, where it was unable to transcribe genes encoding its target proteins, many of which have tumor-suppressive activities. These findings suggest that Src-JNK activity in tumors predicts Notch activity status and that suppressing Src-JNK signaling could restore Notch function in tumors, offering opportunities for diagnosis and targeted therapies for a subset of patients with advanced prostate cancer.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2023-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71487961","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