Pub Date : 2024-02-27DOI: 10.1126/scisignal.ado8046
Leslie K. Ferrarelli
Targeting a driver of TBK1 kinase activity may slow the growth of kidney tumors.
靶向 TBK1 激酶活性的驱动因素可能会减缓肾脏肿瘤的生长。
{"title":"A way to block TBK1 in ccRCC","authors":"Leslie K. Ferrarelli","doi":"10.1126/scisignal.ado8046","DOIUrl":"10.1126/scisignal.ado8046","url":null,"abstract":"<div >Targeting a driver of TBK1 kinase activity may slow the growth of kidney tumors.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139984321","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 : 2024-02-20DOI: 10.1126/scisignal.adc9662
Francis Baumgartner, Stefanos A. Bamopoulos, Laura Faletti, Hsiang-Jung Hsiao, Maximilian Holz, Irene Gonzalez-Menendez, Llorenç Boldo, Arik Horne, Sanket Gosavi, Ceren Özerdem, Nikita Singh, Sven Liebig, Senthilkumar Ramamoorthy, Malte Lehmann, Uta Demel, Anja A. Kühl, Tim Wartewig, Jürgen Ruland, Frank T. Wunderlich, Markus Schick, Wolfgang Walther, Stefan Rose-John, Simon Haas, Leticia Quintanilla-Martinez, Stefan Feske, Stephan Ehl, Rainer Glauben, Ulrich Keller
The IL-6–gp130–STAT3 signaling axis is a major regulator of inflammation. Activating mutations in the gene encoding gp130 and germline gain-of-function mutations in STAT3 (STAT3GOF) are associated with multi-organ autoimmunity, severe morbidity, and adverse prognosis. To dissect crucial cellular subsets and disease biology involved in activated gp130 signaling, the gp130-JAK-STAT3 axis was constitutively activated using a transgene, L-gp130, specifically targeted to T cells. Activating gp130 signaling in T cells in vivo resulted in fatal, early onset, multi-organ autoimmunity in mice that resembled human STAT3GOF disease. Female mice had more rapid disease progression than male mice. On a cellular level, gp130 signaling induced the activation and effector cell differentiation of T cells, promoted the expansion of T helper type 17 (TH17) cells, and impaired the activity of regulatory T cells. Transcriptomic profiling of CD4+ and CD8+ T cells from these mice revealed commonly dysregulated genes and a gene signature that, when applied to human transcriptomic data, improved the segregation of patients with transcriptionally diverse STAT3GOF mutations from healthy controls. The findings demonstrate that increased gp130-STAT3 signaling leads to TH17-driven autoimmunity that phenotypically resembles human STAT3GOF disease.
IL-6-gp130-STAT3 信号轴是炎症的主要调节因子。编码 gp130 基因的激活突变和 STAT3 基因的功能增益突变（STAT3GOF）与多器官自身免疫、严重发病和不良预后有关。为了剖析活化的 gp130 信号所涉及的关键细胞亚群和疾病生物学特性，研究人员利用转基因 L-gp130 对 T 细胞进行了特异性靶向，从而构成性地激活了 gp130-JAK-STAT3 轴。激活体内 T 细胞中的 gp130 信号导致小鼠出现致命的、早发的多器官自身免疫疾病，这种疾病类似于人类的 STAT3GOF 疾病。与雄性小鼠相比，雌性小鼠的病情发展更快。在细胞水平上，gp130 信号诱导了 T 细胞的活化和效应细胞分化，促进了 17 型 T 辅助细胞（TH17）的扩增，并损害了调节性 T 细胞的活性。对这些小鼠的 CD4+ 和 CD8+ T 细胞进行转录组分析，发现了常见的失调基因和基因特征，将其应用于人类转录组数据时，能更好地将转录多样的 STAT3GOF 突变患者与健康对照组区分开来。研究结果表明，gp130-STAT3 信号的增加会导致 TH17 驱动的自身免疫，其表型与人类 STAT3GOF 疾病相似。
{"title":"Activation of gp130 signaling in T cells drives TH17-mediated multi-organ autoimmunity","authors":"Francis Baumgartner, Stefanos A. Bamopoulos, Laura Faletti, Hsiang-Jung Hsiao, Maximilian Holz, Irene Gonzalez-Menendez, Llorenç Boldo, Arik Horne, Sanket Gosavi, Ceren Özerdem, Nikita Singh, Sven Liebig, Senthilkumar Ramamoorthy, Malte Lehmann, Uta Demel, Anja A. Kühl, Tim Wartewig, Jürgen Ruland, Frank T. Wunderlich, Markus Schick, Wolfgang Walther, Stefan Rose-John, Simon Haas, Leticia Quintanilla-Martinez, Stefan Feske, Stephan Ehl, Rainer Glauben, Ulrich Keller","doi":"10.1126/scisignal.adc9662","DOIUrl":"10.1126/scisignal.adc9662","url":null,"abstract":"<div >The IL-6–gp130–STAT3 signaling axis is a major regulator of inflammation. Activating mutations in the gene encoding gp130 and germline gain-of-function mutations in STAT3 (STAT3<sup>GOF</sup>) are associated with multi-organ autoimmunity, severe morbidity, and adverse prognosis. To dissect crucial cellular subsets and disease biology involved in activated gp130 signaling, the gp130-JAK-STAT3 axis was constitutively activated using a transgene, <i>L-gp130</i>, specifically targeted to T cells. Activating gp130 signaling in T cells in vivo resulted in fatal, early onset, multi-organ autoimmunity in mice that resembled human STAT3<sup>GOF</sup> disease. Female mice had more rapid disease progression than male mice. On a cellular level, gp130 signaling induced the activation and effector cell differentiation of T cells, promoted the expansion of T helper type 17 (T<sub>H</sub>17) cells, and impaired the activity of regulatory T cells. Transcriptomic profiling of CD4<sup>+</sup> and CD8<sup>+</sup> T cells from these mice revealed commonly dysregulated genes and a gene signature that, when applied to human transcriptomic data, improved the segregation of patients with transcriptionally diverse STAT3<sup>GOF</sup> mutations from healthy controls. The findings demonstrate that increased gp130-STAT3 signaling leads to T<sub>H</sub>17-driven autoimmunity that phenotypically resembles human STAT3<sup>GOF</sup> disease.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139913943","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 : 2024-02-20DOI: 10.1126/scisignal.adg9256
Yueh-Chien Lin, Steven Swendeman, Irina S. Moreira, Avishek Ghosh, Andrew Kuo, Nícia Rosário-Ferreira, Shihui Guo, Alan Culbertson, Michel V. Levesque, Andreane Cartier, Takahiro Seno, Alec Schmaier, Sylvain Galvani, Asuka Inoue, Samir M. Parikh, Garret A. FitzGerald, David Zurakowski, Maofu Liao, Robert Flaumenhaft, Zeynep H. Gümüş, Timothy Hla
High-density lipoprotein (HDL) nanoparticles promote endothelial cell (EC) function and suppress inflammation, but their utility in treating EC dysfunction has not been fully explored. Here, we describe a fusion protein named ApoA1-ApoM (A1M) consisting of apolipoprotein A1 (ApoA1), the principal structural protein of HDL that forms lipid nanoparticles, and ApoM, a chaperone for the bioactive lipid sphingosine 1-phosphate (S1P). A1M forms HDL-like particles, binds to S1P, and is signaling competent. Molecular dynamics simulations showed that the S1P-bound ApoM moiety in A1M efficiently activated EC surface receptors. Treatment of human umbilical vein ECs with A1M-S1P stimulated barrier function either alone or cooperatively with other barrier-enhancing molecules, including the stable prostacyclin analog iloprost, and suppressed cytokine-induced inflammation. A1M-S1P injection into mice during sterile inflammation suppressed neutrophil influx and inflammatory mediator secretion. Moreover, systemic A1M administration led to a sustained increase in circulating HDL-bound S1P and suppressed inflammation in a murine model of LPS-induced endotoxemia. We propose that A1M administration may enhance vascular endothelial barrier function, suppress cytokine storm, and promote resilience of the vascular endothelium.
{"title":"Designer high-density lipoprotein particles enhance endothelial barrier function and suppress inflammation","authors":"Yueh-Chien Lin, Steven Swendeman, Irina S. Moreira, Avishek Ghosh, Andrew Kuo, Nícia Rosário-Ferreira, Shihui Guo, Alan Culbertson, Michel V. Levesque, Andreane Cartier, Takahiro Seno, Alec Schmaier, Sylvain Galvani, Asuka Inoue, Samir M. Parikh, Garret A. FitzGerald, David Zurakowski, Maofu Liao, Robert Flaumenhaft, Zeynep H. Gümüş, Timothy Hla","doi":"10.1126/scisignal.adg9256","DOIUrl":"10.1126/scisignal.adg9256","url":null,"abstract":"<div >High-density lipoprotein (HDL) nanoparticles promote endothelial cell (EC) function and suppress inflammation, but their utility in treating EC dysfunction has not been fully explored. Here, we describe a fusion protein named ApoA1-ApoM (A1M) consisting of apolipoprotein A1 (ApoA1), the principal structural protein of HDL that forms lipid nanoparticles, and ApoM, a chaperone for the bioactive lipid sphingosine 1-phosphate (S1P). A1M forms HDL-like particles, binds to S1P, and is signaling competent. Molecular dynamics simulations showed that the S1P-bound ApoM moiety in A1M efficiently activated EC surface receptors. Treatment of human umbilical vein ECs with A1M-S1P stimulated barrier function either alone or cooperatively with other barrier-enhancing molecules, including the stable prostacyclin analog iloprost, and suppressed cytokine-induced inflammation. A1M-S1P injection into mice during sterile inflammation suppressed neutrophil influx and inflammatory mediator secretion. Moreover, systemic A1M administration led to a sustained increase in circulating HDL-bound S1P and suppressed inflammation in a murine model of LPS-induced endotoxemia. We propose that A1M administration may enhance vascular endothelial barrier function, suppress cytokine storm, and promote resilience of the vascular endothelium.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139913944","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 : 2024-02-20DOI: 10.1126/scisignal.ado6463
John F. Foley
The efficacy of therapeutic T cells is enhanced by incorporating mutations associated with autoimmunity or lymphoma.
将与自身免疫或淋巴瘤有关的突变纳入治疗性 T 细胞，可提高其疗效。
{"title":"Poachers turned gamekeepers in T cells","authors":"John F. Foley","doi":"10.1126/scisignal.ado6463","DOIUrl":"10.1126/scisignal.ado6463","url":null,"abstract":"<div >The efficacy of therapeutic T cells is enhanced by incorporating mutations associated with autoimmunity or lymphoma.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139913945","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 : 2024-02-13DOI: 10.1126/scisignal.ado4078
Wei Wong
Glycated RNAs on neutrophils enable adhesion to the endothelium and extravasation to sites of inflammation.
中性粒细胞上的糖化 RNA 可使其粘附到血管内皮，并外渗到炎症部位。
{"title":"RNAs create a sticky situation","authors":"Wei Wong","doi":"10.1126/scisignal.ado4078","DOIUrl":"10.1126/scisignal.ado4078","url":null,"abstract":"<div >Glycated RNAs on neutrophils enable adhesion to the endothelium and extravasation to sites of inflammation.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139730829","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 : 2024-02-13DOI: 10.1126/scisignal.abl5880
Tharindunee Jayakody, Asuka Inoue, Srinivasaraghavan Kannan, Gaku Nakamura, Kouki Kawakami, Krishan Mendis, Thanh-Binh Nguyen, Jianguo Li, Deron R. Herr, Chandra S. Verma, Gavin S. Dawe
The neuropeptide relaxin-3 is composed of an A chain and a B chain held together by disulfide bonds, and it modulates functions such as anxiety and food intake by binding to and activating its cognate receptor RXFP3, mainly through the B chain. Biased ligands of RXFP3 would help to determine the molecular mechanisms underlying the activation of G proteins and β-arrestins downstream of RXFP3 that lead to such diverse functions. We showed that the i, i+4 stapled relaxin-3 B chains, 14s18 and d(1-7)14s18, were Gαi/o-biased agonists of RXFP3. These peptides did not induce recruitment of β-arrestin1/2 to RXFP3 by GPCR kinases (GRKs), in contrast to relaxin-3, which enabled the GRK2/3-mediated recruitment of β-arrestin1/2 to RXFP3. Relaxin-3 and the previously reported peptide 4 (an i, i+4 stapled relaxin-3 B chain) did not exhibit biased signaling. The staple linker of peptide 4 and parts of both the A chain and B chain of relaxin-3 interacted with extracellular loop 3 (ECL3) of RXFP3, moving it away from the binding pocket, suggesting that unbiased ligands promote a more open conformation of RXFP3. These findings highlight roles for the A chain and the N-terminal residues of the B chain of relaxin-3 in inducing conformational changes in RXFP3, which will help in designing selective biased ligands with improved therapeutic efficacy.
神经肽松弛素-3 由二硫键连接的 A 链和 B 链组成，它主要通过 B 链与同源受体 RXFP3 结合并激活 RXFP3，从而调节焦虑和食物摄入等功能。RXFP3 的偏向配体将有助于确定 RXFP3 下游 G 蛋白和 β-阻遏素激活的分子机制，从而实现如此多样的功能。我们的研究表明，i、i+4 订书钉弛缓素-3 B 链 14s18 和 d(1-7)14s18 是 RXFP3 的 Gαi/o 偏向激动剂。这些多肽不能诱导 GPCR 激酶（GRKs）将 β-阿restin1/2 募集到 RXFP3 上，而松弛素-3 则能使 GRK2/3 介导的 β-阿restin1/2 募集到 RXFP3 上。弛缓素-3 和之前报道的多肽 4（i, i+4 短链弛缓素-3 B 链）没有表现出偏向性信号传导。肽 4 的主链连接体以及弛缓素-3 的 A 链和 B 链的一部分与 RXFP3 的胞外环 3（ECL3）相互作用，使其远离结合口袋，这表明无偏配体能促进 RXFP3 形成更开放的构象。这些发现强调了弛缓素-3的A链和B链的N端残基在诱导RXFP3构象变化中的作用，这将有助于设计具有更好疗效的选择性偏向配体。
{"title":"Mechanisms of biased agonism by Gαi/o-biased stapled peptide agonists of the relaxin-3 receptor","authors":"Tharindunee Jayakody, Asuka Inoue, Srinivasaraghavan Kannan, Gaku Nakamura, Kouki Kawakami, Krishan Mendis, Thanh-Binh Nguyen, Jianguo Li, Deron R. Herr, Chandra S. Verma, Gavin S. Dawe","doi":"10.1126/scisignal.abl5880","DOIUrl":"10.1126/scisignal.abl5880","url":null,"abstract":"<div >The neuropeptide relaxin-3 is composed of an A chain and a B chain held together by disulfide bonds, and it modulates functions such as anxiety and food intake by binding to and activating its cognate receptor RXFP3, mainly through the B chain. Biased ligands of RXFP3 would help to determine the molecular mechanisms underlying the activation of G proteins and β-arrestins downstream of RXFP3 that lead to such diverse functions. We showed that the i, i+4 stapled relaxin-3 B chains, 14s18 and d(1-7)14s18, were Gα<sub>i/o</sub>-biased agonists of RXFP3. These peptides did not induce recruitment of β-arrestin1/2 to RXFP3 by GPCR kinases (GRKs), in contrast to relaxin-3, which enabled the GRK2/3-mediated recruitment of β-arrestin1/2 to RXFP3. Relaxin-3 and the previously reported peptide 4 (an i, i+4 stapled relaxin-3 B chain) did not exhibit biased signaling. The staple linker of peptide 4 and parts of both the A chain and B chain of relaxin-3 interacted with extracellular loop 3 (ECL3) of RXFP3, moving it away from the binding pocket, suggesting that unbiased ligands promote a more open conformation of RXFP3. These findings highlight roles for the A chain and the N-terminal residues of the B chain of relaxin-3 in inducing conformational changes in RXFP3, which will help in designing selective biased ligands with improved therapeutic efficacy.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.abl5880","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139730828","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 : 2024-02-13DOI: 10.1126/scisignal.add9139
Julia Gardner, Dylan Scott Eiger, Chloe Hicks, Issac Choi, Uyen Pham, Anand Chundi, Ojas Namjoshi, Sudarshan Rajagopal
Some G protein–coupled receptors (GPCRs) demonstrate biased signaling such that ligands of the same receptor exclusively or preferentially activate certain downstream signaling pathways over others. This phenomenon may result from ligand-specific receptor phosphorylation by GPCR kinases (GRKs). GPCR signaling can also exhibit location bias because GPCRs traffic to and signal from subcellular compartments in addition to the plasma membrane. Here, we investigated whether GRKs contributed to location bias in GPCR signaling. GRKs translocated to endosomes after stimulation of the chemokine receptor CXCR3 or other GPCRs in cultured cells. GRK2, GRK3, GRK5, and GRK6 showed distinct patterns of recruitment to the plasma membrane and to endosomes depending on the identity of the biased ligand used to activate CXCR3. Analysis of engineered forms of GRKs that localized to either the plasma membrane or endosomes demonstrated that biased CXCR3 ligands elicited different signaling profiles that depended on the subcellular location of the GRK. Each GRK exerted a distinct effect on the regulation of CXCR3 engagement of β-arrestin, internalization, and activation of the downstream effector kinase ERK. Our work highlights a role for GRKs in location-biased GPCR signaling and demonstrates the complex interactions between ligands, GRKs, and cellular location that contribute to biased signaling.
{"title":"GPCR kinases differentially modulate biased signaling downstream of CXCR3 depending on their subcellular localization","authors":"Julia Gardner, Dylan Scott Eiger, Chloe Hicks, Issac Choi, Uyen Pham, Anand Chundi, Ojas Namjoshi, Sudarshan Rajagopal","doi":"10.1126/scisignal.add9139","DOIUrl":"10.1126/scisignal.add9139","url":null,"abstract":"<div >Some G protein–coupled receptors (GPCRs) demonstrate biased signaling such that ligands of the same receptor exclusively or preferentially activate certain downstream signaling pathways over others. This phenomenon may result from ligand-specific receptor phosphorylation by GPCR kinases (GRKs). GPCR signaling can also exhibit location bias because GPCRs traffic to and signal from subcellular compartments in addition to the plasma membrane. Here, we investigated whether GRKs contributed to location bias in GPCR signaling. GRKs translocated to endosomes after stimulation of the chemokine receptor CXCR3 or other GPCRs in cultured cells. GRK2, GRK3, GRK5, and GRK6 showed distinct patterns of recruitment to the plasma membrane and to endosomes depending on the identity of the biased ligand used to activate CXCR3. Analysis of engineered forms of GRKs that localized to either the plasma membrane or endosomes demonstrated that biased CXCR3 ligands elicited different signaling profiles that depended on the subcellular location of the GRK. Each GRK exerted a distinct effect on the regulation of CXCR3 engagement of β-arrestin, internalization, and activation of the downstream effector kinase ERK. Our work highlights a role for GRKs in location-biased GPCR signaling and demonstrates the complex interactions between ligands, GRKs, and cellular location that contribute to biased signaling.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139730827","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 : 2024-02-06DOI: 10.1126/scisignal.abq1007
Ismael Izquierdo-Villalba, Serena Mirra, Yasmina Manso, Antoni Parcerisas, Javier Rubio, Jaume Del Valle, Francisco J. Gil-Bea, Fausto Ulloa, Marina Herrero-Lorenzo, Ester Verdaguer, Cristiane Benincá, Rubén D. Castro-Torres, Elena Rebollo, Gemma Marfany, Carme Auladell, Xavier Navarro, José A. Enríquez, Adolfo López de Munain, Eduardo Soriano, Anna M. Aragay
Mitochondrial dynamics and trafficking are essential to provide the energy required for neurotransmission and neural activity. We investigated how G protein–coupled receptors (GPCRs) and G proteins control mitochondrial dynamics and trafficking. The activation of Gαq inhibited mitochondrial trafficking in neurons through a mechanism that was independent of the canonical downstream PLCβ pathway. Mitoproteome analysis revealed that Gαq interacted with the Eutherian-specific mitochondrial protein armadillo repeat–containing X-linked protein 3 (Alex3) and the Miro1/Trak2 complex, which acts as an adaptor for motor proteins involved in mitochondrial trafficking along dendrites and axons. By generating a CNS-specific Alex3 knockout mouse line, we demonstrated that Alex3 was required for the effects of Gαq on mitochondrial trafficking and dendritic growth in neurons. Alex3-deficient mice had altered amounts of ER stress response proteins, increased neuronal death, motor neuron loss, and severe motor deficits. These data revealed a mammalian-specific Alex3/Gαq mitochondrial complex, which enables control of mitochondrial trafficking and neuronal death by GPCRs.
线粒体的动态和贩运对于提供神经传递和神经活动所需的能量至关重要。我们研究了 G 蛋白偶联受体（GPCR）和 G 蛋白如何控制线粒体的动态和贩运。Gαq 的激活通过一种独立于典型下游 PLCβ 通路的机制抑制了神经元中线粒体的贩运。有丝分裂蛋白组分析表明，Gαq与卢瑟人特异性线粒体蛋白含犰狳重复的X连锁蛋白3（Alex3）和Miro1/Trak2复合体相互作用，后者是参与线粒体沿树突和轴突迁移的运动蛋白的适配体。通过产生中枢神经系统特异性 Alex3 基因敲除小鼠品系，我们证明了 Gαq 对线粒体贩运和神经元树突生长的影响需要 Alex3 的参与。Alex3缺陷小鼠体内ER应激反应蛋白的数量发生改变，神经元死亡增加，运动神经元缺失，并出现严重的运动障碍。这些数据揭示了哺乳动物特异性的Alex3/Gαq线粒体复合体，它能够通过GPCR控制线粒体的运输和神经元的死亡。
{"title":"A mammalian-specific Alex3/Gαq protein complex regulates mitochondrial trafficking, dendritic complexity, and neuronal survival","authors":"Ismael Izquierdo-Villalba, Serena Mirra, Yasmina Manso, Antoni Parcerisas, Javier Rubio, Jaume Del Valle, Francisco J. Gil-Bea, Fausto Ulloa, Marina Herrero-Lorenzo, Ester Verdaguer, Cristiane Benincá, Rubén D. Castro-Torres, Elena Rebollo, Gemma Marfany, Carme Auladell, Xavier Navarro, José A. Enríquez, Adolfo López de Munain, Eduardo Soriano, Anna M. Aragay","doi":"10.1126/scisignal.abq1007","DOIUrl":"10.1126/scisignal.abq1007","url":null,"abstract":"<div >Mitochondrial dynamics and trafficking are essential to provide the energy required for neurotransmission and neural activity. We investigated how G protein–coupled receptors (GPCRs) and G proteins control mitochondrial dynamics and trafficking. The activation of Gα<sub>q</sub> inhibited mitochondrial trafficking in neurons through a mechanism that was independent of the canonical downstream PLCβ pathway. Mitoproteome analysis revealed that Gα<sub>q</sub> interacted with the Eutherian-specific mitochondrial protein armadillo repeat–containing X-linked protein 3 (Alex3) and the Miro1/Trak2 complex, which acts as an adaptor for motor proteins involved in mitochondrial trafficking along dendrites and axons. By generating a CNS-specific Alex3 knockout mouse line, we demonstrated that Alex3 was required for the effects of Gα<sub>q</sub> on mitochondrial trafficking and dendritic growth in neurons. Alex3-deficient mice had altered amounts of ER stress response proteins, increased neuronal death, motor neuron loss, and severe motor deficits. These data revealed a mammalian-specific Alex3/Gα<sub>q</sub> mitochondrial complex, which enables control of mitochondrial trafficking and neuronal death by GPCRs.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139698702","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 : 2024-02-06DOI: 10.1126/scisignal.adh0439
Joel Eggert, Wendy M. Zinzow-Kramer, Yuesong Hu, Elizabeth M. Kolawole, Yuan-Li Tsai, Arthur Weiss, Brian D. Evavold, Khalid Salaita, Christopher D. Scharer, Byron B. Au-Yeung
Naive T cells experience tonic T cell receptor (TCR) signaling in response to self-antigens presented by major histocompatibility complex (MHC) in secondary lymphoid organs. We investigated how relatively weak or strong tonic TCR signals influence naive CD8+ T cell responses to stimulation with foreign antigens. The heterogeneous expression of Nur77-GFP, a transgenic reporter of tonic TCR signaling, in naive CD8+ T cells suggests variable intensities or durations of tonic TCR signaling. Although the expression of genes associated with acutely stimulated T cells was increased in Nur77-GFPHI cells, these cells were hyporesponsive to agonist TCR stimulation compared with Nur77-GFPLO cells. This hyporesponsiveness manifested as diminished activation marker expression and decreased secretion of IFN-γ and IL-2. The protein abundance of the ubiquitin ligase Cbl-b, a negative regulator of TCR signaling, was greater in Nur77-GFPHI cells than in Nur77-GFPLO cells, and Cbl-b deficiency partially restored the responsiveness of Nur77-GFPHI cells. Our data suggest that the cumulative effects of previously experienced tonic TCR signaling recalibrate naive CD8+ T cell responsiveness. These changes include gene expression changes and negative regulation partially dependent on Cbl-b. This cell-intrinsic negative feedback loop may enable the immune system to restrain naive CD8+ T cells with higher self-reactivity.
天真 T 细胞在对次级淋巴器官中由主要组织相容性复合体（MHC）呈现的自身抗原做出反应时，会出现强直性 T 细胞受体（TCR）信号。我们研究了相对较弱或较强的强直性 TCR 信号如何影响天真 CD8+ T 细胞对外来抗原刺激的反应。Nur77-GFP 是强直性 TCR 信号转导的转基因报告物，它在幼稚 CD8+ T 细胞中的异质性表达表明，强直性 TCR 信号转导的强度或持续时间各不相同。虽然 Nur77-GFPHI 细胞中与急性刺激 T 细胞相关的基因表达增加，但与 Nur77-GFPLO 细胞相比，这些细胞对激动剂 TCR 刺激的反应较低。这种低反应性表现为活化标志物表达减少以及 IFN-γ 和 IL-2 分泌减少。泛素连接酶 Cbl-b 是 TCR 信号转导的负调控因子，它在 Nur77-GFPHI 细胞中的蛋白丰度高于 Nur77-GFPLO 细胞，而 Cbl-b 的缺乏部分恢复了 Nur77-GFPHI 细胞的反应性。我们的数据表明，先前经历的强直性 TCR 信号的累积效应重新校准了天真 CD8+ T 细胞的反应性。这些变化包括基因表达变化和部分依赖于 Cbl-b 的负调控。这种细胞内在的负反馈环路可能会使免疫系统抑制自我反应性更高的幼稚 CD8+ T 细胞。
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