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Identification of proteins in semen-derived extracellular vesicles that bind to Tat and NF-κB and that may impair HIV replication 精液源性细胞外囊泡中与Tat和NF-κB结合并可能损害HIV复制的蛋白质的鉴定

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-09-09 DOI: 10.1126/scisignal.ado9243

Bryson C. Okeoma, Hussein Kaddour, Wasifa Naushad, Victor Paromov, Ashok Chaudhary, Alessio Noghero, Jack T. Stapleton, Chioma M. Okeoma

Replication of HIV-1 requires the coordinated action of host and viral transcription factors, most critically the viral transactivator Tat and the host nuclear factor κB (NF-κB). This activity is disrupted in infected cells that are cultured with extracellular vesicles (EVs) present in human semen, suggesting that they contain factors that could inform the development of new therapeutics. Here, we explored the contents of semen-derived EVs (SEVs) from uninfected donors and individuals with HIV-1 and identified host proteins that interacted with HIV Tat and the NF-κB subunit p65. Integrative network and pathway enrichment analyses of these complexes revealed associations with an array of biological functions regulating gene expression. Several proteins in SEVs bound to both Tat and NF-κB p65: the scaffolding and cell signaling regulatory protein AKAP9, the G protein signaling regulator ARHGEF28, the epigenetic reader BRD2, the small nuclear RNA processor INTS1, and the transcription elongation inhibitor NELFB. When complexed with p65, NELFB also interacted with HEXIM1, another transcription elongation inhibitor, suggesting that SEVs may inhibit HIV-1 propagation through multiple networks of transcriptional activation and repression. Exploring these data and the underlying mechanisms may inform the development of more effective or more durable therapeutics against HIV.

HIV-1的复制需要宿主和病毒转录因子的协同作用，最关键的是病毒反激活因子Tat和宿主核因子κB （NF-κB）。在与人类精液中存在的细胞外囊泡（ev）培养的受感染细胞中，这种活性被破坏，这表明它们含有可能为新疗法的开发提供信息的因素。在这里，我们研究了来自未感染供体和HIV-1患者的精液源性ev （sev）的含量，并鉴定了与HIV Tat和NF-κB亚基p65相互作用的宿主蛋白。这些复合物的综合网络和通路富集分析揭示了与一系列调节基因表达的生物学功能的关联。sev中与Tat和NF-κB p65结合的蛋白包括：支架和细胞信号调节蛋白AKAP9、G蛋白信号调节蛋白ARHGEF28、表观遗传读取器BRD2、小核RNA处理器INTS1和转录延伸抑制剂NELFB。当与p65结合时，NELFB还与另一种转录延伸抑制剂HEXIM1相互作用，这表明sev可能通过多个转录激活和抑制网络抑制HIV-1的传播。探索这些数据和潜在机制可能为开发更有效或更持久的艾滋病毒治疗方法提供信息。

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引用次数: 0

Fusobacterium nucleatum enhances amphetamine-induced behavioral responses through a butyrate-driven epigenetic mechanism 核梭杆菌通过丁酸盐驱动的表观遗传机制增强安非他明诱导的行为反应

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-09-09 DOI: 10.1126/scisignal.adx7729

Samuel J. Mabry, Xixi Cao, Yanqi Zhu, Caleb Rowe, Shalin Patel, Camila González-Arancibia, Tiziana Romanazzi, David P. Saleeby, Anna Elam, Hui-Ting Lee, Serhat Turkmen, Shelby N. Lauzon, Cesar E. Hernandez, HaoSheng Sun, Hui Wu, Angela M. Carter, Aurelio Galli

Amphetamines are psychostimulants that are commonly used to treat neuropsychiatric disorders and are prone to misuse. The pathogenesis of amphetamine use disorder (AUD) is associated with dysbiosis (an imbalance in the body’s microbiome) and bacterially produced short-chain fatty acids (SCFAs), which are implicated in the gut-brain axis. Amphetamine exposure in both rats and humans increases the amount of intestinal Fusobacterium nucleatum, which releases SFCAs. Here, we found that colonization of gnotobiotic Drosophila melanogaster with F. nucleatum or supplementing the flies’ diet with the SCFA butyrate enhanced the psychomotor and reward properties of amphetamine. Butyrate inhibits histone deacetylases (HDACs), and knockdown of HDAC1 recapitulated the effects induced by F. nucleatum or butyrate. The enhancement in amphetamine-induced behaviors was mediated by an increase in the amount of released dopamine that resulted from amphetamine-induced reversal of dopamine transporter (DAT) function, termed nonvesicular dopamine release (NVDR). The magnitude of amphetamine-induced NVDR was partially mediated by an increase in DAT abundance stimulated at a transcriptional level, and the administration of F. nucleatum or butyrate enhanced NVDR by increasing DAT expression. The findings indicate that F. nucleatum supports AUD through epigenetic regulation of dopamine signaling and identify potential targets for AUD treatment.

安非他明是一种精神兴奋剂，通常用于治疗神经精神疾病，容易被滥用。安非他明使用障碍（AUD）的发病机制与生态失调（体内微生物组的不平衡）和细菌产生的短链脂肪酸（SCFAs）有关，后者与肠脑轴有关。在大鼠和人体内暴露安非他明会增加肠道核梭杆菌的数量，而核梭杆菌会释放SFCAs。本研究发现，将黑腹果蝇定植于有核梭菌或在果蝇的饮食中添加丁酸SCFA可增强安非他明的精神运动和奖励特性。丁酸盐抑制组蛋白去乙酰化酶（HDACs），而HDAC1的敲低再现了核仁梭菌或丁酸盐诱导的作用。安非他明诱导的行为增强是由安非他明诱导的多巴胺转运体（DAT）功能逆转（称为非囊性多巴胺释放（NVDR））导致的多巴胺释放量增加介导的。安非他明诱导的NVDR的程度部分是由转录水平上刺激的DAT丰度增加介导的，而核仁梭菌或丁酸盐通过增加DAT表达来增强NVDR。研究结果表明，核梭菌通过多巴胺信号的表观遗传调控支持AUD，并确定了AUD治疗的潜在靶点。

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引用次数: 0

APOE ε4 on immunity APOE ε4对免疫的影响

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-09-09 DOI: 10.1126/scisignal.aec0130

Leslie K. Ferrarelli

APOE ε4 dysregulates systemic immunity, creating vulnerability for neurodegenerative disease.

APOE ε4失调全身免疫，造成神经退行性疾病的易感性。

引用次数: 0

MAPK and mTORC1 signaling converge to drive cyclin D1 protein production to enable cell cycle reentry in melanoma persister cells MAPK和mTORC1信号汇聚驱动细胞周期蛋白D1蛋白的产生，从而使黑色素瘤持续细胞重新进入细胞周期

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-09-02 DOI: 10.1126/scisignal.adw3231

Varuna Nangia, Humza Ashraf, Nasreen Marikar, Victor J. Passanisi, Christopher R. Ill, Sabrina L. Spencer

In BRAF-mutant melanoma cells treated with inhibitors of the kinases BRAF and MEK, a subset of cells rapidly and nongenetically adapts to escape drug-induced quiescence and reenters the cell cycle. Here, we investigated the mechanisms enabling this drug escape by computationally reconstructing single-cell lineages from time-lapse imaging data, linking dynamic signaling pathways to distinct cell-cycle fate outcomes. We found that reactivation of the MEK substrate ERK was necessary but not sufficient to drive escape; rather, the activity of the protein complex mTORC1 was also required to promote cell growth and protein synthesis in drug-treated cells destined for cell-cycle reentry. ERK and mTORC1 signaling converged to increase the abundance of cyclin D1 protein, a critical bottleneck for cell-cycle commitment under drug pressure. In cells in which endogenous cyclin D1 was fluorescently tagged using CRISPR, the subset that escaped drug treatment exhibited marked accumulation of cyclin D1 at least 15 hours before cell-cycle reentry, enabling early prediction of future drug escape. Cyclin D1 thus represents both an early biomarker and potential therapeutic target for suppressing drug escape in melanoma. We observed a similar mTORC1-driven mechanism underlying escape in lung cancer cells, but not colon cancer cells, highlighting partial generalizability across cancer types.

在BRAF突变的黑色素瘤细胞中，用BRAF和MEK激酶抑制剂治疗，细胞亚群迅速和非遗传性地适应逃避药物诱导的静止并重新进入细胞周期。在这里，我们通过计算重建单细胞谱系，从延时成像数据中研究了这种药物逃逸的机制，将动态信号通路与不同的细胞周期命运结果联系起来。我们发现MEK底物ERK的再激活是必要的，但不足以驱动逃逸；相反，蛋白质复合物mTORC1的活性也需要促进细胞生长和蛋白质合成的药物处理细胞的细胞周期返回。ERK和mTORC1信号融合增加了cyclin D1蛋白的丰度，这是药物压力下细胞周期承诺的关键瓶颈。在使用CRISPR荧光标记内源性细胞周期蛋白D1的细胞中，逃避药物治疗的细胞亚群在细胞周期再进入前至少15小时表现出明显的细胞周期蛋白D1积累，从而能够早期预测未来的药物逃逸。因此，Cyclin D1既是早期生物标志物，也是抑制黑色素瘤药物逃逸的潜在治疗靶点。我们在肺癌细胞中观察到类似的mtorc1驱动的逃逸机制，但在结肠癌细胞中却没有，这突出了癌症类型的部分普遍性。

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引用次数: 0

Gαq signaling in primary sensory neurons shifts opioid analgesia to NMDA receptor–driven tolerance and hyperalgesia 初级感觉神经元中的Gαq信号将阿片镇痛转变为NMDA受体驱动的耐受和痛觉过敏

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-09-02 DOI: 10.1126/scisignal.adu8839

Daozhong Jin, Hong Chen, Meng-Hua Zhou, Yuying Huang, Shao-Rui Chen, Hui-Lin Pan

Opioids relieve pain by activating μ-opioid receptors (MORs), which inhibit communication between pain-sensing neurons (nociceptors) and the spinal cord. However, prolonged opioid use can paradoxically lead to increased pain sensitivity (hyperalgesia) and reduced analgesic efficacy (tolerance), partly because of the activation of NMDA-type glutamate receptors (NMDARs) at the central terminals of primary sensory neurons in the spinal cord. Here, we identified a critical role for the G protein Gα_q in this paradox. Pharmacological inhibition of Gα_q in rats reversed morphine-induced increases in NMDAR phosphorylation, synaptic trafficking, and activity at sensory neuron terminals and reduced morphine-induced excitatory nociceptive input to spinal dorsal horn neurons. Morphine enhanced Gα_q coupling specifically to metabotropic glutamate receptor 5 (mGluR5) dimers in the spinal cord. Furthermore, targeted knockdown of Gα_q in dorsal root ganglion neurons in mice normalized NMDAR-related changes and prevented NMDAR-mediated synaptic potentiation triggered by MOR activation. In addition, either pharmacological or genetic disruption of Gα_q signaling enhanced morphine’s analgesic effects while reducing hyperalgesia and tolerance. These findings reveal that Gα_q signaling contributes to opioid-induced NMDAR hyperactivity at nociceptor central terminals by promoting MOR-mGluR5 cross-talk. Targeting this pathway may improve the safety and efficacy of opioid-based pain management.

阿片类药物通过激活μ-阿片受体（MORs）来缓解疼痛，而μ-阿片受体抑制痛觉神经元（痛觉感受器）与脊髓之间的交流。然而，长期使用阿片类药物可能会导致疼痛敏感性增加（痛觉过敏）和镇痛效果降低（耐受性），部分原因是脊髓初级感觉神经元中央末端的nmda型谷氨酸受体（NMDARs）被激活。在这里，我们确定了G蛋白Gαq在这一悖论中的关键作用。大鼠Gαq的药理抑制逆转了吗啡诱导的NMDAR磷酸化、突触运输和感觉神经元末梢活性的增加，并减少了吗啡诱导的脊髓背角神经元的兴奋性伤害性输入。吗啡增强了g - αq与脊髓中代谢性谷氨酸受体5 （mGluR5）二聚体特异性偶联。此外，靶向下调小鼠背根神经节神经元Gαq可使nmdar相关变化正常化，并阻止nmdar介导的MOR激活引发的突触增强。此外，g - αq信号的药理或遗传破坏增强了吗啡的镇痛作用，同时降低了痛觉过敏和耐受性。这些发现表明，Gαq信号通过促进MOR-mGluR5串扰，参与阿片类药物诱导的伤害感受器中枢末端NMDAR亢进。靶向这一途径可能提高阿片类药物疼痛管理的安全性和有效性。

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引用次数: 0

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

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

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

Annalisa M. VanHook

Estrogen protects against kidney injury through both genomic and nongenomic mechanisms.

雌激素通过基因组和非基因组机制保护肾脏免受损伤。

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 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

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

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 Escherichia coli genome encodes at least 150 small proteins, most of which are functionally uncharacterized. We identified and characterized 17 small proteins induced in E. coli during magnesium (Mg²⁺) 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 Mg²⁺ homeostasis. Deletion or overexpression of some of these small proteins led to growth defects and changes in cell size under low-Mg²⁺ 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 Mg²⁺ limitation independently of yoaI 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.

细菌小蛋白（≤50个氨基酸）是一类新兴的调节因子，可调节信号网络的活性，使细菌适应压力。大肠杆菌基因组编码至少150种小蛋白质，其中大多数在功能上未被表征。通过核糖体分析、RNA测序和转录报告基因分析，我们鉴定并鉴定了大肠杆菌在镁（Mg2+）饥饿期间诱导的17个小蛋白。其中一些是由PhoQ-PhoP双组分信号系统转录激活的，这对Mg2+的稳态至关重要。在低mg2 +条件下，其中一些小蛋白的缺失或过表达导致生长缺陷和细胞大小的变化，表明在逆境适应中的生理作用。小跨膜蛋白YoaI在Mg2+限制下丰度增加，而不受YoaI转录或PhoQ-PhoP信号通路的影响。youai激活了第三个信号系统EnvZ-OmpR，该系统介导对渗透胁迫的反应。总的来说，本研究建立了一个初步框架，以了解小蛋白如何通过促进不同信号系统之间的串扰来促进细菌的应激适应。我们的研究结果表明，这些蛋白质在协调应激反应中发挥更广泛的作用，反映了细胞应激网络的相互联系性质，而不是对特定应激源作出反应的严格划分的途径。

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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 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

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

Three amylin receptors (AMYRs) mediate the metabolic actions of the peptide hormone amylin and are drug targets for diabetes and obesity. AMY₁R, AMY₂R, and AMY₃R 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 AMY₁R and AMY₂R subunit distributions favored free CTR and RAMPs and that rat amylin promoted association of the constituent subunits of AMY₁R and AMY₂R. The agonist αCGRP also induced AMY₁R subunit association. A stronger interaction between the CTR and the RAMP3 transmembrane domains yielded a more stable AMY₃R, and human and salmon calcitonin agonists promoted AMY₃R 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.

三种amylin受体（AMYRs）介导肽激素amylin的代谢作用，是糖尿病和肥胖症的药物靶点。AMY1R、AMY2R和AMY3R是由降钙素受体（CTR）组成的异源二聚体，CTR是一种G蛋白偶联受体，分别与RAMP1、RAMP2或RAMP3辅助亚基配对，可以增加胰淀粉酶的效力。在这里，我们发现amyr具有不同的基础亚基平衡，由肽激动剂调节，并决定了受体激活下游cAMP信号的程度。通过开发一种生化分析来分辨AMYR异源二聚体和游离亚基，我们发现AMY1R和AMY2R亚基分布有利于游离CTR和RAMPs，大鼠amylin促进AMY1R和AMY2R组成亚基的关联。激动剂α - cgrp也能诱导AMY1R亚基关联。CTR和RAMP3跨膜结构域之间更强的相互作用产生了更稳定的AMY3R，人和鲑鱼降钙素激动剂促进了AMY3R的解离。在活细胞膜中观察到亚基结合和解离的类似变化，G蛋白偶联和cAMP信号分析显示了这些变化如何改变信号传导。我们的研究结果对AMYR生物学和药物开发具有重要意义，并揭示了通过亚基相互作用动力学调控异质GPCR信号传导。

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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 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

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

Noradrenaline released from sympathetic neurons accelerates cancer metastasis by activating β₂-adrenergic receptors (β₂-adrenoceptors) on tumor cells to promote invasion. We previously showed that the β₂-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 β₂-adrenoceptor. Integrated analysis of transcriptomic datasets revealed HOXC12, 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 HOXC12 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 HOXC12 prevented β₂-adrenoceptor–mediated calcium signaling and invasion in cultured TNBC cells. In basal breast cancers, HOXC12 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 β₂-adrenoceptor–responsive TNBC cells.

交感神经元释放的去甲肾上腺素通过激活肿瘤细胞上的β2-肾上腺素能受体（β2-adrenoceptors）促进肿瘤侵袭，从而加速肿瘤转移。我们之前的研究表明，β2-肾上腺素能受体通过激活cAMP和钙介导的前馈回路，促进转移性三阴性乳腺癌（TNBC）细胞系的侵袭行为。在这里，我们在大多数具有活性β2-肾上腺素受体的TNBC细胞系中发现了这种机制。转录组学数据集的综合分析显示，编码发育同源盒转录因子的HOXC12是区分有前馈环和没有前馈环的细胞系最具区别性的基因。HOXC12的高表达与cAMP或钙信号相关的整体蛋白的转录变化无关，免疫染色显示HOXC12的胞质定位，表明其发挥非转录作用。敲除HOXC12可阻止β2-肾上腺素受体介导的钙信号传导和TNBC细胞的侵袭。在基础乳腺癌中，HOXC12在肿瘤中的表达与患者的总生存期和无病生存期呈负相关。这些发现确定了在β2-肾上腺素受体应答的TNBC细胞中cAMP和钙信号驱动的侵袭协调中的关键介质Hox-C12。

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引用次数: 0

Tailored receptor modulators 定制受体调节剂

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

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

John F. Foley

Positive allosteric modulators of free fatty acid receptor 2 induce distinct conformations to bias G protein signaling.

游离脂肪酸受体2的正变构调节剂诱导不同构象偏向G蛋白信号。

引用次数: 0

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