Pub Date : 2025-12-23DOI: 10.1126/scisignal.aee7080
Annalisa M. VanHook
A bacterial virulence factor subverts host cell apoptosis by acting as a protein recombinase.
细菌毒力因子通过作为蛋白质重组酶破坏宿主细胞凋亡。
{"title":"Shigella mixes and matches host proteins","authors":"Annalisa M. VanHook","doi":"10.1126/scisignal.aee7080","DOIUrl":"10.1126/scisignal.aee7080","url":null,"abstract":"<div >A bacterial virulence factor subverts host cell apoptosis by acting as a protein recombinase.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 918","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145808793","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 : 2025-12-23DOI: 10.1126/scisignal.adv0660
Nicholas M. Venetos, Colin T. Stomberski, Hua-Lin Zhou, Zhaoxia Qian, Precious J. McLaughlin, Puneet K. Bansal, John Feczko, Ilya Bederman, Hoa Nguyen, Alfred Hausladen, Joseph C. Schindler, Zachary W. Grimmett, Henri Brunengraber, Richard T. Premont, Jonathan S. Stamler
Lipid homeostasis is subject to control by posttranslational modification machinery, such as sirtuin deacetylases that reverse coenzyme A (CoA)–dependent acetylation. Here, we showed that a mammalian denitrosylase (SCoR2), which counteracts CoA-dependent S-nitrosylation, promoted both fat storage and lipogenesis to impair metabolic health. In mice, SCoR2 protein abundance correlated with body mass, and deleting or pharmacologically inhibiting SCoR2 prevented both diet-induced obesity and metabolic dysfunction–associated steatotic liver disease (MASLD). Loss of SCoR2 in adipocytes promoted the S-nitrosylation of the actin cytoskeletal regulator myosin 9, which inhibited the activity of the lipogenesis-promoting transcription factors PPARγ, SREBP1, and CEBPα to prevent fat storage. In hepatocytes, inhibition of SCoR2-mediated denitrosylation of lipogenic enzymes reduced fat synthesis and induced fat oxidation. In humans, an obesity-linked polymorphism was associated with increased SCoR2 mRNA expression, and in patient adipose and liver tissues, SCoR2 protein or mRNA abundance directly correlated with adipocyte size or MASLD. These results indicate that SCoR2 regulates nutrient metabolism, similar to sirtuins, and is a potential drug target for obesity and MASLD.
{"title":"The protein denitrosylase SCoR2 regulates lipogenesis and fat storage","authors":"Nicholas M. Venetos, Colin T. Stomberski, Hua-Lin Zhou, Zhaoxia Qian, Precious J. McLaughlin, Puneet K. Bansal, John Feczko, Ilya Bederman, Hoa Nguyen, Alfred Hausladen, Joseph C. Schindler, Zachary W. Grimmett, Henri Brunengraber, Richard T. Premont, Jonathan S. Stamler","doi":"10.1126/scisignal.adv0660","DOIUrl":"10.1126/scisignal.adv0660","url":null,"abstract":"<div >Lipid homeostasis is subject to control by posttranslational modification machinery, such as sirtuin deacetylases that reverse coenzyme A (CoA)–dependent acetylation. Here, we showed that a mammalian denitrosylase (SCoR2), which counteracts CoA-dependent S-nitrosylation, promoted both fat storage and lipogenesis to impair metabolic health. In mice, SCoR2 protein abundance correlated with body mass, and deleting or pharmacologically inhibiting SCoR2 prevented both diet-induced obesity and metabolic dysfunction–associated steatotic liver disease (MASLD). Loss of <i>SCoR2</i> in adipocytes promoted the S-nitrosylation of the actin cytoskeletal regulator myosin 9, which inhibited the activity of the lipogenesis-promoting transcription factors PPARγ, SREBP1, and CEBPα to prevent fat storage. In hepatocytes, inhibition of SCoR2-mediated denitrosylation of lipogenic enzymes reduced fat synthesis and induced fat oxidation. In humans, an obesity-linked polymorphism was associated with increased <i>SCoR2</i> mRNA expression, and in patient adipose and liver tissues, SCoR2 protein or mRNA abundance directly correlated with adipocyte size or MASLD. These results indicate that SCoR2 regulates nutrient metabolism, similar to sirtuins, and is a potential drug target for obesity and MASLD.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 918","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145808796","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 : 2025-12-16DOI: 10.1126/scisignal.ady8676
Landon M. Lin, Marcelo Febo, Adriaan W. Bruijnzeel, Leah Phan, Adithya Gopinath, Jordan Seibold, Emily Miller, Habibeh Khoshbouei
The highly addictive psychostimulant methamphetamine increases the release of dopamine in the brain’s reward circuitry, where it also promotes the release of cytokines, including TNF-α, that contribute to neuroinflammation associated with methamphetamine abuse. Here, we found a dynamic interplay between methamphetamine and TNF-α in facilitating dopamine transmission within the ventral tegmental area (VTA) in mice. In ex vivo mouse brain slices and dopaminergic neurons, methamphetamine or TNF-α treatment increased dopamine release, intracellular Ca2+ concentrations, and the firing activity of VTA dopaminergic neurons. These effects depended on the activity of dopamine transporter (DAT) and L-type voltage-gated Ca2+ channels. Pharmacological inhibition of either DAT or TNF-α signaling mitigated these effects, suggesting that methamphetamine-induced alterations in VTA dopaminergic neurons are partially TNF-α dependent. These results underscore the role of neuroimmune signaling in modulating the dopaminergic circuitry and may inform therapeutic strategies for addressing methamphetamine addiction and its associated neuroinflammatory disorders.
{"title":"TNF-α signaling mediates the dopaminergic effects of methamphetamine by stimulating dopamine transporters and L-type Ca2+ channels","authors":"Landon M. Lin, Marcelo Febo, Adriaan W. Bruijnzeel, Leah Phan, Adithya Gopinath, Jordan Seibold, Emily Miller, Habibeh Khoshbouei","doi":"10.1126/scisignal.ady8676","DOIUrl":"10.1126/scisignal.ady8676","url":null,"abstract":"<div >The highly addictive psychostimulant methamphetamine increases the release of dopamine in the brain’s reward circuitry, where it also promotes the release of cytokines, including TNF-α, that contribute to neuroinflammation associated with methamphetamine abuse. Here, we found a dynamic interplay between methamphetamine and TNF-α in facilitating dopamine transmission within the ventral tegmental area (VTA) in mice. In ex vivo mouse brain slices and dopaminergic neurons, methamphetamine or TNF-α treatment increased dopamine release, intracellular Ca<sup>2+</sup> concentrations, and the firing activity of VTA dopaminergic neurons. These effects depended on the activity of dopamine transporter (DAT) and L-type voltage-gated Ca<sup>2+</sup> channels. Pharmacological inhibition of either DAT or TNF-α signaling mitigated these effects, suggesting that methamphetamine-induced alterations in VTA dopaminergic neurons are partially TNF-α dependent. These results underscore the role of neuroimmune signaling in modulating the dopaminergic circuitry and may inform therapeutic strategies for addressing methamphetamine addiction and its associated neuroinflammatory disorders.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 917","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145761524","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 : 2025-12-16DOI: 10.1126/scisignal.adu4315
Aqfan Jamaluddin, Rachael A. Wyatt, Joon Lee, Georgina K. C. Dowsett, John A. Tadross, Johannes Broichhagen, Giles S. H. Yeo, Joshua Levitz, Caroline M. Gorvin
The central melanocortin system links nutrition to energy expenditure. Melanocortin-4 receptor (MC4R) controls appetite and food intake, and its signaling is potentiated by melanocortin-2 receptor accessory protein 2 (MRAP2). Human mutations in MC4R and MRAP2 are associated with obesity. Here, we sought to determine whether MRAP2 affected the activity of MC3R, which is structurally similar to MC4R and which regulates sexual maturation, linear growth rate, and lean mass accumulation. Single-molecule pull-down assays showed that MC3R and MRAP2 interacted in HEK293 cells. Analysis of fluorescence photobleaching steps showed that MC3R and MRAP2 readily formed heterodimers, most commonly with a 1:1 stoichiometry. Mining of previously published human single-nucleus and spatial transcriptomic data showed coexpression of MRAP2 and MC3R in hypothalamic neurons that function in energy homeostasis and appetite control. In HEK293 cells, MRAP2 enhanced cAMP signaling downstream of MC3R, impaired β-arrestin recruitment to MC3R, and reduced MC3R internalization. The ability of MRAP2 to promote MC3R signaling was suppressed by alanine mutagenesis of five MRAP2 and two MC3R transmembrane residues identified by structural homology models as important for the interaction. We showed that variants of MRAP2 found in individuals who are overweight or obese did not enhance MC3R-driven signaling. Thus, these studies implicate MRAP2 as an important regulator of MC3R function and provide further evidence for the crucial role of MRAP2 in energy homeostasis.
黑素皮质素中枢系统将营养与能量消耗联系起来。黑素皮质素-4受体（Melanocortin-4 receptor, MC4R）控制食欲和食物摄入，其信号传导由黑素皮质素-2受体辅助蛋白2 （melanocortin-2 receptor accessory protein 2, MRAP2）增强。人类MC4R和MRAP2基因突变与肥胖有关。在这里，我们试图确定MRAP2是否影响MC3R的活性，MC3R在结构上与MC4R相似，并调节性成熟、线性生长速度和瘦质量积累。单分子下拉实验显示MC3R和MRAP2在HEK293细胞中相互作用。荧光光漂白步骤分析表明，MC3R和MRAP2很容易形成异源二聚体，最常见的是1:1的化学计量。对先前发表的人类单核和空间转录组数据的挖掘显示，MRAP2和MC3R在下丘脑神经元中共表达，在能量稳态和食欲控制中起作用。在HEK293细胞中，MRAP2增强了MC3R下游的cAMP信号，破坏了β-阻滞蛋白向MC3R的募集，并减少了MC3R内化。MRAP2促进MC3R信号传导的能力被结构同源模型鉴定的5个MRAP2和2个MC3R跨膜残基的丙氨酸突变所抑制，这些残基对相互作用很重要。我们发现，在超重或肥胖个体中发现的MRAP2变异并没有增强mc3r驱动的信号传导。因此，这些研究提示MRAP2是MC3R功能的重要调节因子，并为MRAP2在能量稳态中的关键作用提供了进一步的证据。
{"title":"The accessory protein MRAP2 directly interacts with melanocortin-3 receptor to enhance signaling","authors":"Aqfan Jamaluddin, Rachael A. Wyatt, Joon Lee, Georgina K. C. Dowsett, John A. Tadross, Johannes Broichhagen, Giles S. H. Yeo, Joshua Levitz, Caroline M. Gorvin","doi":"10.1126/scisignal.adu4315","DOIUrl":"10.1126/scisignal.adu4315","url":null,"abstract":"<div >The central melanocortin system links nutrition to energy expenditure. Melanocortin-4 receptor (MC4R) controls appetite and food intake, and its signaling is potentiated by melanocortin-2 receptor accessory protein 2 (MRAP2). Human mutations in <i>MC4R</i> and <i>MRAP2</i> are associated with obesity. Here, we sought to determine whether MRAP2 affected the activity of MC3R, which is structurally similar to MC4R and which regulates sexual maturation, linear growth rate, and lean mass accumulation. Single-molecule pull-down assays showed that MC3R and MRAP2 interacted in HEK293 cells. Analysis of fluorescence photobleaching steps showed that MC3R and MRAP2 readily formed heterodimers, most commonly with a 1:1 stoichiometry. Mining of previously published human single-nucleus and spatial transcriptomic data showed coexpression of <i>MRAP2</i> and <i>MC3R</i> in hypothalamic neurons that function in energy homeostasis and appetite control. In HEK293 cells, MRAP2 enhanced cAMP signaling downstream of MC3R, impaired β-arrestin recruitment to MC3R, and reduced MC3R internalization. The ability of MRAP2 to promote MC3R signaling was suppressed by alanine mutagenesis of five MRAP2 and two MC3R transmembrane residues identified by structural homology models as important for the interaction. We showed that variants of MRAP2 found in individuals who are overweight or obese did not enhance MC3R-driven signaling. Thus, these studies implicate MRAP2 as an important regulator of MC3R function and provide further evidence for the crucial role of MRAP2 in energy homeostasis.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 917","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145761523","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 : 2025-12-09DOI: 10.1126/scisignal.ado2768
Akashdip Singh, Saskia V. Vijver, Hajar Aglmous-Talibi, Nebojsa Jukic, Peirong Chen, Suzanne Crawley, Kalyani Mondal, Jing Zhou, Christian Niederauer, Zimple Matharu, Betty Li, Bin Fan, Michiel van der Vlist, Daniel D. Kaplan, Lee B. Rivera, James Sissons, Jonathan Sitrin, Kristina A. Ganzinger, M. Inês Pascoal Ramos, Linde Meyaard
LAIR-1 is an inhibitory receptor on immune cells that recognizes collagens and collagen domain–containing proteins. The high abundance of both LAIR-1 and its ligands suggests tight regulation of this interaction. MARCO is a scavenger receptor with a collagen-like domain that is highly expressed on immunosuppressive macrophages. Here, we identified MARCO as a ligand for LAIR-1. MARCO interacted with LAIR-1 in trans and induced inhibitory signaling by LAIR-1 in human natural killer (NK) cells. MARCO and LAIR-1 were coexpressed by human macrophages in tumors and after stimulation of monocyte-derived macrophages with the cytokine interleukin-10 (IL-10) in vitro. Single-molecule fluorescence microscopy demonstrated that MARCO and LAIR-1 interacted in cis on THP-1 macrophages. Whereas the interaction did not affect the scavenger function of MARCO on human macrophages, it reduced both LAIR-1 binding and the LAIR-1 signaling response to collagen. LAIR-1–mediated inhibitory function was increased after CRISPR-Cas9–mediated knockout of MARCO in IL-10–polarized primary human monocyte-derived macrophages. Our results identify MARCO as a regulator of LAIR-1 signaling and suggest that the induction of MARCO on immunosuppressive macrophages could enhance their function by releasing LAIR-1–mediated inhibition.
{"title":"The scavenger receptor MARCO is a ligand for the immune inhibitory receptor LAIR-1 and regulates its function in cis","authors":"Akashdip Singh, Saskia V. Vijver, Hajar Aglmous-Talibi, Nebojsa Jukic, Peirong Chen, Suzanne Crawley, Kalyani Mondal, Jing Zhou, Christian Niederauer, Zimple Matharu, Betty Li, Bin Fan, Michiel van der Vlist, Daniel D. Kaplan, Lee B. Rivera, James Sissons, Jonathan Sitrin, Kristina A. Ganzinger, M. Inês Pascoal Ramos, Linde Meyaard","doi":"10.1126/scisignal.ado2768","DOIUrl":"10.1126/scisignal.ado2768","url":null,"abstract":"<div >LAIR-1 is an inhibitory receptor on immune cells that recognizes collagens and collagen domain–containing proteins. The high abundance of both LAIR-1 and its ligands suggests tight regulation of this interaction. MARCO is a scavenger receptor with a collagen-like domain that is highly expressed on immunosuppressive macrophages. Here, we identified MARCO as a ligand for LAIR-1. MARCO interacted with LAIR-1 in trans and induced inhibitory signaling by LAIR-1 in human natural killer (NK) cells. MARCO and LAIR-1 were coexpressed by human macrophages in tumors and after stimulation of monocyte-derived macrophages with the cytokine interleukin-10 (IL-10) in vitro. Single-molecule fluorescence microscopy demonstrated that MARCO and LAIR-1 interacted in cis on THP-1 macrophages. Whereas the interaction did not affect the scavenger function of MARCO on human macrophages, it reduced both LAIR-1 binding and the LAIR-1 signaling response to collagen. LAIR-1–mediated inhibitory function was increased after CRISPR-Cas9–mediated knockout of MARCO in IL-10–polarized primary human monocyte-derived macrophages. Our results identify MARCO as a regulator of LAIR-1 signaling and suggest that the induction of MARCO on immunosuppressive macrophages could enhance their function by releasing LAIR-1–mediated inhibition.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 916","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145706674","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 : 2025-12-09DOI: 10.1126/scisignal.adp7760
Kwun Nok Mimi Man, Sarah L. S. Rougé, Ruben A. Berumen, Ariel A. Jacobi, Justin C. Weiner, Shawheen Y. Naderi, Kyle E. Ireton, Zoila M. Estrada-Tobar, Zhuoer Zeng, Joseph M. Martinez, Yang K. Xiang, Madeline Nieves-Cintrón, Manuel F. Navedo, Peter Bartels, Mary C. Horne, Johannes W. Hell
Dopamine drives the neuronal activity and synaptic plasticity required for various forms of learning. It supports short-term working memory through activation of the D1-like dopamine receptors D1 and D5. Here, we found that the L-type Ca2+ channel CaV1.2 was a critical mediator of D1/5 signaling in hippocampal pyramidal neurons. In cultured mouse hippocampal neurons, a D1/5 agonist augmented currents through CaV1.2 in the soma and Ca2+ influx in the dendrites. This effect was mediated through the second messenger cAMP and cAMP-dependent protein kinase (PKA), which phosphorylated the CaV1.2 α1 subunit at Ser1928. CaV1.2 and D5 colocalized, suggesting that this signaling was spatially restricted. In mice, D1/5 agonism facilitated spatial working memory in wild-type but not litter-matched CaV1.2 α1 S1928A knockin animals. These findings identify CaV1.2 as a key D1/5 signaling effector that supports dopamine-driven executive functions in cognition.
{"title":"Stimulation of Ca2+ channel CaV1.2 activity by dopamine signaling augments spatial working memory","authors":"Kwun Nok Mimi Man, Sarah L. S. Rougé, Ruben A. Berumen, Ariel A. Jacobi, Justin C. Weiner, Shawheen Y. Naderi, Kyle E. Ireton, Zoila M. Estrada-Tobar, Zhuoer Zeng, Joseph M. Martinez, Yang K. Xiang, Madeline Nieves-Cintrón, Manuel F. Navedo, Peter Bartels, Mary C. Horne, Johannes W. Hell","doi":"10.1126/scisignal.adp7760","DOIUrl":"10.1126/scisignal.adp7760","url":null,"abstract":"<div >Dopamine drives the neuronal activity and synaptic plasticity required for various forms of learning. It supports short-term working memory through activation of the D<sub>1</sub>-like dopamine receptors D<sub>1</sub> and D<sub>5</sub>. Here, we found that the L-type Ca<sup>2+</sup> channel Ca<sub>V</sub>1.2 was a critical mediator of D<sub>1/5</sub> signaling in hippocampal pyramidal neurons. In cultured mouse hippocampal neurons, a D<sub>1/5</sub> agonist augmented currents through Ca<sub>V</sub>1.2 in the soma and Ca<sup>2+</sup> influx in the dendrites. This effect was mediated through the second messenger cAMP and cAMP-dependent protein kinase (PKA), which phosphorylated the Ca<sub>V</sub>1.2 α<sub>1</sub> subunit at Ser<sup>1928</sup>. Ca<sub>V</sub>1.2 and D<sub>5</sub> colocalized, suggesting that this signaling was spatially restricted. In mice, D<sub>1/5</sub> agonism facilitated spatial working memory in wild-type but not litter-matched Ca<sub>V</sub>1.2 α<sub>1</sub> S1928A knockin animals. These findings identify Ca<sub>V</sub>1.2 as a key D<sub>1/5</sub> signaling effector that supports dopamine-driven executive functions in cognition.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 916","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adp7760","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145706673","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 : 2025-12-02DOI: 10.1126/scisignal.adw2270
Weiwei Zhang, Nilay Kumar, Jessica R. Helwig, Alexis Hoerter, Anjali S. Iyer-Pascuzzi, David M. Umulis, Elsje Pienaar, Christopher J. Staiger
Cytosolic calcium ion (Ca2+) signatures with specific spatiotemporal patterns play crucial roles in plant responses to biotic and abiotic stresses. The perception of microbe- or damage-associated molecular patterns (MAMPs or DAMPs, respectively) initiates cytosolic Ca2+ fluxes that are essential for the induction and spread of pattern-triggered immunity, the first line of plant defense against pathogens, at the cellular, organ, and systemic levels. Here, we quantitatively assessed Ca2+ signatures at the single-cell level, as well as the local traveling Ca2+ waves induced by uniform MAMP or DAMP treatment of Arabidopsis thaliana cotyledons. MAMPs and DAMPs induced distinct local spatiotemporal Ca2+ responses in epidermal pavement cells, with traveling waves of Ca2+ consistently initiated from a randomly distributed subset of cells and spreading in an approximately radial pattern. These local traveling waves propagated at a slow but constant speed of ~1 micrometer per second and spread to a limited number of neighboring cells. In contrast, wound-induced traveling waves of Ca2+, which are propagated by the diffusion of molecules that activate Ca2+ channels, displayed a diffusion-like decay pattern that moved rapidly away from the wounded cell but with diminishing speed over time and distance. Mathematical modeling supported a Ca2+-induced Ca2+ release mechanism that recapitulated the constant wave speed induced by MAMPs. These findings contribute to a deeper understanding of plant defense–related Ca2+ signaling mechanisms, as well as how defense responses are spatially restricted in tissues.
{"title":"Local traveling waves of cytosolic Ca2+ elicited by defense signals or wounding are propagated by distinct mechanisms in Arabidopsis","authors":"Weiwei Zhang, Nilay Kumar, Jessica R. Helwig, Alexis Hoerter, Anjali S. Iyer-Pascuzzi, David M. Umulis, Elsje Pienaar, Christopher J. Staiger","doi":"10.1126/scisignal.adw2270","DOIUrl":"10.1126/scisignal.adw2270","url":null,"abstract":"<div >Cytosolic calcium ion (Ca<sup>2+</sup>) signatures with specific spatiotemporal patterns play crucial roles in plant responses to biotic and abiotic stresses. The perception of microbe- or damage-associated molecular patterns (MAMPs or DAMPs, respectively) initiates cytosolic Ca<sup>2+</sup> fluxes that are essential for the induction and spread of pattern-triggered immunity, the first line of plant defense against pathogens, at the cellular, organ, and systemic levels. Here, we quantitatively assessed Ca<sup>2+</sup> signatures at the single-cell level, as well as the local traveling Ca<sup>2+</sup> waves induced by uniform MAMP or DAMP treatment of <i>Arabidopsis thaliana</i> cotyledons. MAMPs and DAMPs induced distinct local spatiotemporal Ca<sup>2+</sup> responses in epidermal pavement cells, with traveling waves of Ca<sup>2+</sup> consistently initiated from a randomly distributed subset of cells and spreading in an approximately radial pattern. These local traveling waves propagated at a slow but constant speed of ~1 micrometer per second and spread to a limited number of neighboring cells. In contrast, wound-induced traveling waves of Ca<sup>2+</sup>, which are propagated by the diffusion of molecules that activate Ca<sup>2+</sup> channels, displayed a diffusion-like decay pattern that moved rapidly away from the wounded cell but with diminishing speed over time and distance. Mathematical modeling supported a Ca<sup>2+</sup>-induced Ca<sup>2+</sup> release mechanism that recapitulated the constant wave speed induced by MAMPs. These findings contribute to a deeper understanding of plant defense–related Ca<sup>2+</sup> signaling mechanisms, as well as how defense responses are spatially restricted in tissues.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 915","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145652869","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 : 2025-12-02DOI: 10.1126/scisignal.adt8890
Marlene Fritsche, Gaia Picozzi, Tomas Nyman, Hugo Zeberg, Richard Ågren
G protein–coupled receptors (GPCRs) play key roles in neurodevelopment by regulating excitatory and inhibitory neuronal pathways. The G protein subunit Gαi1 is a downstream effector of inhibitory GPCR signaling, and the gene encoding it (GNAI1) is abundantly expressed in the brain. Rare GNAI1 variants are linked to a severe neurodevelopmental disorder called GNAI1 syndrome, which is characterized by intellectual disability, a range of movement issues, and epilepsy. Here, we investigated the effect of five GNAI1 syndrome–associated missense variants on GPCR signaling. Predictions based on genetic biobank data and in silico modeling suggested that these variants were pathogenic. Compared with the wild-type protein, four Gαi1 variants (T48K, T48I, C224Y, and V332E) showed marked increases in dopamine potency at the dopamine D2 receptor (D2R) and increased constitutive G protein activity when expressed in Xenopus laevis oocytes. By contrast, the Gαi1 G40C variant was unresponsive to D2R activation. All Gαi1 variants displayed reduced GTP-γ-S binding rates and undetectable GTP hydrolysis, except for the T48I variant, which showed more rapid binding and hydrolysis. Thus, four GNAI1 syndrome variants caused a net gain-of-function effect on D2R signaling, and all studied variants disrupted GTP exchange. These biochemical effects may underlie GNAI1 syndrome, and GNAI1 mutations should therefore be considered when screening for rare neurodevelopmental disorders.
{"title":"GNAI1 missense mutations associated with a neurodevelopmental syndrome modify Gαi1 function","authors":"Marlene Fritsche, Gaia Picozzi, Tomas Nyman, Hugo Zeberg, Richard Ågren","doi":"10.1126/scisignal.adt8890","DOIUrl":"10.1126/scisignal.adt8890","url":null,"abstract":"<div >G protein–coupled receptors (GPCRs) play key roles in neurodevelopment by regulating excitatory and inhibitory neuronal pathways. The G protein subunit Gα<sub>i1</sub> is a downstream effector of inhibitory GPCR signaling, and the gene encoding it (<i>GNAI1</i>) is abundantly expressed in the brain. Rare <i>GNAI1</i> variants are linked to a severe neurodevelopmental disorder called <i>GNAI1</i> syndrome, which is characterized by intellectual disability, a range of movement issues, and epilepsy. Here, we investigated the effect of five <i>GNAI1</i> syndrome–associated missense variants on GPCR signaling. Predictions based on genetic biobank data and in silico modeling suggested that these variants were pathogenic. Compared with the wild-type protein, four Gα<sub>i1</sub> variants (T48K, T48I, C224Y, and V332E) showed marked increases in dopamine potency at the dopamine D2 receptor (D2R) and increased constitutive G protein activity when expressed in <i>Xenopus laevis</i> oocytes. By contrast, the Gα<sub>i1</sub> G40C variant was unresponsive to D2R activation. All Gα<sub>i1</sub> variants displayed reduced GTP-γ-S binding rates and undetectable GTP hydrolysis, except for the T48I variant, which showed more rapid binding and hydrolysis. Thus, four <i>GNAI1</i> syndrome variants caused a net gain-of-function effect on D2R signaling, and all studied variants disrupted GTP exchange. These biochemical effects may underlie <i>GNAI1</i> syndrome, and <i>GNAI1</i> mutations should therefore be considered when screening for rare neurodevelopmental disorders.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 915","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145652870","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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