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HIV-1 Vpu and SARS-CoV-2 ORF3a proteins disrupt STING-mediated activation of antiviral NF-κB signaling

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-01-21 DOI: 10.1126/scisignal.add6593

Yajuan Rui, Si Shen, Yanpu Wang, Leyi Cheng, Shiqi Chen, Ying Hu, Yong Cai, Wei Wei, Jiaming Su, Xiao-Fang Yu

Activation of the stimulator of interferon genes (STING) pathway by cytosolic DNA leads to the activation of the transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB). Although many viruses produce proteins that inhibit IRF3-dependent antiviral responses, some viruses produce proteins that inhibit STING-induced NF-κB activation without blocking IRF3 activation. Here, we found that STING-activated, NF-κB–dependent, and IRF3-independent innate immunity inhibited the replication of the DNA virus herpes simplex virus type 1 (HSV-1), the RNA virus coxsackievirus A16 (CV-A16), and the retrovirus HIV-1. The HIV-1 nonstructural protein Vpu bound to STING and prevented it from interacting with the upstream NF-κB pathway kinase inhibitor of NF-κB subunit β (IKKβ), thus blocking NF-κB signaling. This function of Vpu was conserved among Vpu proteins from diverse HIV-1 and simian immunodeficiency virus strains and was distinct from its action in disrupting other host antiviral pathways. Furthermore, the ORF3a protein from the coronavirus SARS-CoV-2 also promoted viral replication by interacting with STING and blocking STING-induced activity of NF-κB but not of IRF3. These findings demonstrate that diverse viral proteins have convergently evolved to selectively inhibit NF-κB–mediated innate immunity downstream of STING activation, suggesting that targeting this pathway may represent a promising antiviral strategy.

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引用次数: 0

Biotin mitigates the development of manganese-induced, Parkinson’s disease–related neurotoxicity in Drosophila and human neurons

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-01-21 DOI: 10.1126/scisignal.adn9868

Yunjia Lai, Pablo Reina-Gonzalez, Gali Maor, Gary W. Miller, Souvarish Sarkar

Chronic exposure to manganese (Mn) induces manganism and has been widely implicated as a contributing environmental factor to Parkinson’s disease (PD), featuring notable overlaps between the two in motor symptoms and clinical hallmarks. Here, we developed an adult Drosophila model of Mn toxicity that recapitulated key parkinsonian features, spanning behavioral deficits, neuronal loss, and dysfunctions in lysosomes and mitochondria. Metabolomics analysis of the brain and body tissues of these flies at an early stage of toxicity identified systemic changes in the metabolism of biotin (also known as vitamin B₇) in Mn-treated groups. Biotinidase-deficient flies showed exacerbated Mn-induced neurotoxicity, parkinsonism, and mitochondrial dysfunction. Supplementing the diet of wild-type flies with biotin ameliorated the pathological phenotypes of concurrent exposure to Mn. Biotin supplementation also ameliorated the pathological phenotypes of three standard fly models of PD. Furthermore, supplementing the culture media of human induced stem cells (iPSCs) differentiated midbrain dopaminergic neurons with biotin protected against Mn-induced mitochondrial dysregulation, cytotoxicity, and neuronal loss. Last, analysis of the expression of genes encoding biotin-related proteins in patients with PD revealed increased amounts of biotin transporters in the substantia nigra compared with healthy controls, suggesting a potential role of altered biotin metabolism in PD. Together, our findings identified changes in biotin metabolism as underlying Mn neurotoxicity and parkinsonian pathology in flies, for which dietary biotin supplementation was preventative.

{"title":"Biotin mitigates the development of manganese-induced, Parkinson’s disease–related neurotoxicity in Drosophila and human neurons","authors":"Yunjia Lai, Pablo Reina-Gonzalez, Gali Maor, Gary W. Miller, Souvarish Sarkar","doi":"10.1126/scisignal.adn9868","DOIUrl":"10.1126/scisignal.adn9868","url":null,"abstract":"<div >Chronic exposure to manganese (Mn) induces manganism and has been widely implicated as a contributing environmental factor to Parkinson’s disease (PD), featuring notable overlaps between the two in motor symptoms and clinical hallmarks. Here, we developed an adult <i>Drosophila</i> model of Mn toxicity that recapitulated key parkinsonian features, spanning behavioral deficits, neuronal loss, and dysfunctions in lysosomes and mitochondria. Metabolomics analysis of the brain and body tissues of these flies at an early stage of toxicity identified systemic changes in the metabolism of biotin (also known as vitamin B<sub>7</sub>) in Mn-treated groups. Biotinidase-deficient flies showed exacerbated Mn-induced neurotoxicity, parkinsonism, and mitochondrial dysfunction. Supplementing the diet of wild-type flies with biotin ameliorated the pathological phenotypes of concurrent exposure to Mn. Biotin supplementation also ameliorated the pathological phenotypes of three standard fly models of PD. Furthermore, supplementing the culture media of human induced stem cells (iPSCs) differentiated midbrain dopaminergic neurons with biotin protected against Mn-induced mitochondrial dysregulation, cytotoxicity, and neuronal loss. Last, analysis of the expression of genes encoding biotin-related proteins in patients with PD revealed increased amounts of biotin transporters in the substantia nigra compared with healthy controls, suggesting a potential role of altered biotin metabolism in PD. Together, our findings identified changes in biotin metabolism as underlying Mn neurotoxicity and parkinsonian pathology in flies, for which dietary biotin supplementation was preventative.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"18 870","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143061277","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

Bypassing senescence 绕过衰老。

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-01-21 DOI: 10.1126/scisignal.adv9441

Annalisa M. VanHook

A metabolic switch enables hepatocytes in damaged livers to escape senescence and form tumors.

代谢开关使受损肝脏中的肝细胞免于衰老并形成肿瘤。

引用次数: 0

Conditional requirement for dimerization of the membrane-binding module for BTK signaling in lymphocyte cell lines 淋巴细胞系BTK信号膜结合模块二聚化的条件要求。

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-01-14 DOI: 10.1126/scisignal.ado1252

Timothy J. Eisen, Sam Ghaffari-Kashani, Chien-Lun Hung, Jay T. Groves, Arthur Weiss, John Kuriyan

Bruton’s tyrosine kinase (BTK) is a major drug target in immune cells. The membrane-binding pleckstrin homology and tec homology (PH-TH) domains of BTK are required for signaling. Dimerization of the PH-TH module strongly stimulates the kinase activity of BTK in vitro. Here, we investigated whether BTK dimerizes in cells using the PH-TH module and whether this dimerization is necessary for signaling. To address this question, we developed high-throughput mutagenesis assays for BTK function in Ramos B cells and Jurkat T cells. We measured the fitness costs for thousands of point mutations in the PH-TH module and kinase domain to assess whether dimerization of the PH-TH module and BTK kinase activity were necessary for function. In Ramos cells, we found that neither PH-TH dimerization nor kinase activity was required for BTK signaling. Instead, in Ramos cells, BTK signaling was enhanced by PH-TH module mutations that increased membrane adsorption, even at the cost of reduced PH-TH dimerization. In contrast, in Jurkat cells, we found that BTK signaling depended on both PH-TH dimerization and kinase activity. Evolutionary analysis indicated that BTK proteins in organisms that evolved before the divergence of ray-finned fishes lacked PH-TH dimerization but had active kinase domains, similar to other Tec family kinases. Thus, PH-TH dimerization is a distinct feature of BTK that evolved to exert stricter regulatory control on kinase activity as adaptive immune systems gained increased complexity.

布鲁顿酪氨酸激酶（BTK）是免疫细胞的主要药物靶点。BTK的膜结合pleckstrin同源性和tec同源性（PH-TH）结构域是信号转导所必需的。PH-TH模块的二聚化在体外强烈刺激BTK的激酶活性。在这里，我们研究了BTK是否在细胞中使用PH-TH模块二聚化，以及这种二聚化是否为信号传导所必需。为了解决这个问题，我们在Ramos B细胞和Jurkat T细胞中开发了BTK功能的高通量诱变试验。我们测量了PH-TH模块和激酶结构域中数千个点突变的适应度成本，以评估PH-TH模块的二聚化和BTK激酶活性是否对功能是必要的。在Ramos细胞中，我们发现BTK信号既不需要PH-TH二聚化也不需要激酶活性。相反，在Ramos细胞中，PH-TH模块突变增加了膜吸附，甚至以降低PH-TH二聚化为代价，也增强了BTK信号。相反，在Jurkat细胞中，我们发现BTK信号同时依赖于PH-TH二聚化和激酶活性。进化分析表明，在鳐鱼分化之前进化的生物中，BTK蛋白缺乏PH-TH二聚化，但具有活性的激酶结构域，与其他Tec家族激酶相似。因此，PH-TH二聚化是BTK的一个明显特征，随着适应性免疫系统的复杂性增加，BTK进化为对激酶活性施加更严格的调节控制。

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引用次数: 0

HSV and a tale of two taus HSV和双关语。

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-01-14 DOI: 10.1126/scisignal.adv8245

Leslie K. Ferrarelli

Tau aggregates around HSV-1 in the brain, but is this pathological, part of an immune response, or both?

大脑中Tau蛋白聚集在HSV-1周围，但这是病理性的，还是免疫反应的一部分，还是两者兼而有之？

引用次数: 0

Repetitive injury induces phenotypes associated with Alzheimer’s disease by reactivating HSV-1 in a human brain tissue model 在人脑组织模型中，重复性损伤通过重新激活HSV-1诱导与阿尔茨海默病相关的表型。

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-01-07 DOI: 10.1126/scisignal.ado6430

Dana M. Cairns, Brooke M. Smiley, Jordan A. Smiley, Yasaman Khorsandian, Marilyn Kelly, Ruth F. Itzhaki, David L. Kaplan

Infection with herpes simplex virus type 1 (HSV-1) in the brains of APOE4 carriers increases the risk of Alzheimer’s disease (AD). We previously found that latent HSV-1 in a three-dimensional in vitro model of APOE4-heterozygous human brain tissue was reactivated in response to neuroinflammation caused by exposure to other pathogens. Because traumatic brain injury also causes neuroinflammation, we surmised that brain injury might similarly reactivate latent HSV-1. Here, we examined the effects of one or more controlled blows to our human brain model in the absence or presence of latent HSV-1 infection. After repeated, mild controlled blows, latently infected tissues showed reactivation of HSV-1; the production and accumulation of β amyloid and phosphorylated tau (which promotes synaptic dysfunction and neurodegeneration); and activated gliosis, which is associated with destructive neuroinflammation. These effects are collectively associated with AD, dementia, and chronic traumatic encephalopathy (CTE) and were increased with additional injury but were absent in mock-infected tissue. Blocking the cytokine IL-1β prevented the induction of amyloid and gliosis in latently infected monolayer cultures after scratch wounding. We thus propose that after repeated mechanical injuries to the brain, such as from direct blows to the head or jarring motions of the head, the resulting reactivation of HSV-1 in the brain may contribute to the development of AD and related diseases in some individuals.

在APOE4携带者的大脑中感染1型单纯疱疹病毒（HSV-1）会增加患阿尔茨海默病（AD）的风险。我们之前发现，apoe4杂合人脑组织三维体外模型中潜伏的HSV-1在暴露于其他病原体引起的神经炎症反应中被重新激活。由于创伤性脑损伤也会引起神经炎症，我们推测脑损伤可能同样会重新激活潜伏的HSV-1。在这里，我们检查了在没有或存在潜伏的HSV-1感染的情况下，一次或多次控制打击对我们的人脑模型的影响。经过反复的轻度控制打击，潜伏感染的组织显示HSV-1的再激活；β淀粉样蛋白和磷酸化tau蛋白的产生和积累（促进突触功能障碍和神经变性）；以及活化的神经胶质瘤，这与破坏性的神经炎症有关。这些影响与阿尔茨海默病、痴呆和慢性创伤性脑病（CTE）共同相关，并随着额外损伤而增加，但在模拟感染组织中不存在。阻断细胞因子IL-1β可防止搔划伤后潜伏感染的单层培养物中淀粉样蛋白和胶质细胞形成。因此，我们提出，在大脑遭受多次机械损伤后，例如头部受到直接撞击或头部剧烈运动，由此导致的HSV-1在大脑中的重新激活可能导致某些个体发生AD和相关疾病。

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引用次数: 0

IRF1 cooperates with ISGF3 or GAF to form innate immune de novo enhancers in macrophages IRF1与ISGF3或GAF协同在巨噬细胞中形成先天免疫新生增强因子。

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-01-07 DOI: 10.1126/scisignal.ado8860

Carolina Chavez, Kelly Lin, Alexis Malveaux, Aleksandr Gorin, Stefanie Brizuela, Quen J. Cheng, Alexander Hoffmann

Macrophages exposed to immune stimuli reprogram their epigenomes to alter their subsequent functions. Exposure to bacterial lipopolysaccharide (LPS) causes widespread nucleosome remodeling and the formation of thousands of de novo enhancers. We dissected the regulatory logic by which the network of interferon regulatory factors (IRFs) induces the opening of chromatin and the formation of de novo enhancers. We found that LPS-activated IRF3 mediated de novo enhancer formation indirectly by activating the type I interferon (IFN)–induced ISGF3. However, ISGF3 was generally needed to collaborate with IRF1, particularly where chromatin was less accessible. At these locations, IRF1 was required for the initial opening of chromatin, with ISGF3 extending accessibility and promoting the deposition of H3K4me1, marking poised enhancers. Because IRF1 expression depends on the transcription factor NF-κB, which is activated in infected but not bystander cells, IRF-regulated enhancers required activation of both the IRF3 and NF-κB branches of the innate immune signaling network. However, type II IFN (IFN-γ), which is typically produced by T cells, may also induce IRF1 expression through the STAT1 homodimer GAF. We showed that, upon IFN-γ stimulation, IRF1 was also responsible for opening inaccessible chromatin sites that could then be exploited by GAF to form de novo enhancers. Together, our results reveal how combinatorial logic gates of IRF1-ISGF3 or IRF1-GAF restrict immune epigenomic memory formation to macrophages exposed to pathogens or IFN-γ–secreting T cells but not bystander macrophages exposed transiently to type I IFN.

暴露于免疫刺激下的巨噬细胞重新编程其表观基因组以改变其后续功能。暴露于细菌脂多糖（LPS）会引起广泛的核小体重塑和数千种新生增强剂的形成。我们剖析了干扰素调节因子（irf）网络诱导染色质打开和新生增强子形成的调控逻辑。我们发现lps激活的IRF3通过激活I型干扰素（IFN）诱导的ISGF3间接介导了新生增强子的形成。然而，ISGF3通常需要与IRF1合作，特别是在染色质不易获得的地方。在这些位置，染色质的初始打开需要IRF1， ISGF3扩展可及性并促进H3K4me1的沉积，标记平衡增强子。由于IRF1的表达依赖于转录因子NF-κB，而NF-κB在感染细胞中被激活，而不是在旁观者细胞中被激活，因此irf调节的增强因子需要激活先天免疫信号网络的IRF3和NF-κB分支。然而，通常由T细胞产生的II型IFN （IFN-γ）也可能通过STAT1同二聚体GAF诱导IRF1表达。我们发现，在IFN-γ刺激下，IRF1也负责打开无法进入的染色质位点，然后GAF可以利用这些位点形成新生增强子。总之，我们的研究结果揭示了IRF1-ISGF3或IRF1-GAF的组合逻辑门如何限制暴露于病原体或IFN-γ分泌T细胞的巨噬细胞的免疫表观基因组记忆形成，而不是短暂暴露于I型IFN的旁观者巨噬细胞。

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引用次数: 0

Erratum for the Research Article “Reciprocal regulation of mTORC1 signaling and ribosomal biosynthesis determines cell cycle progression in activated T cells” by T. Rosenlehner et al. 对 T. Rosenlehner 等人的研究文章 "mTORC1 信号传导和核糖体生物合成的相互调控决定了活化 T 细胞的细胞周期进程 "的勘误。

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2024-12-17 DOI: 10.1126/scisignal.adu7437

引用次数: 0

Bile acid–induced metabolic changes in the colon promote Enterobacteriaceae expansion and associate with dysbiosis in Crohn’s disease 胆汁酸引起的结肠代谢变化会促进肠杆菌扩增，并与克罗恩病的菌群失调有关。

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2024-12-17 DOI: 10.1126/scisignal.adl1786

Ravi Holani, Haggai Bar-Yoseph, Zakhar Krekhno, Antonio Serapio-Palacios, Kyung-Mee Moon, Richard G. Stacey, Katherine A. Donald, Wanyin Deng, Brian Bressler, Armando A. Magaña, Leonard J. Foster, Michael G. Atser, James D. Johnson, Barton Brett Finlay

Bile acids (BAs) affect the growth of potentially pathogenic commensals, including those from the Enterobacteriaceae family, which are frequently overrepresented in inflammatory bowel disease (IBD). BAs are normally reabsorbed in the ileum for recycling and are often increased in the colonic lumina of patients with IBD, including those with Crohn’s disease (CD). Here, we investigated the influence of BAs on gut colonization by Enterobacteriaceae. We found increased abundance of Enterobacteriaceae in the colonic mucosae of patients with CD with a concomitant decrease in the transporters that resorb BAs in the ileum. The increase in Enterobacteriaceae colonization was greater in the colons of patients who had undergone terminal ileum resection compared with those with intact ileum, leading us to hypothesize that BAs promote intestinal colonization by Enterobacteriaceae. Exposure of human colonic epithelial cell lines to BAs reduced mitochondrial respiration, increased oxygen availability, and enhanced the epithelial adherence of several Enterobacteriaceae members. In a publicly available human dataset, mucosal Enterobacteriaceae was negatively associated with the expression of genes related to mitochondrial function. In a murine model, increased intestinal BA availability enhanced colonization by Escherichia coli in a manner that depended on bacterial respiration. Together, our findings demonstrate that BAs reduce mitochondrial respiration in the colon, leading to an increase in oxygen availability that facilitates Enterobacteriaceae colonization. This identification of BAs as facilitators of host-commensal interactions may be relevant to multiple intestinal diseases.

胆汁酸（BAs）影响潜在致病性共生菌的生长，包括那些来自肠杆菌科的共生菌，它们在炎症性肠病（IBD）中经常被过度代表。ba通常在回肠中被重新吸收以进行循环，并且在IBD患者（包括克罗恩病（CD）患者）的结肠腔中经常增加。在这里，我们研究了BAs对肠杆菌科肠道定植的影响。我们发现，乳糜泻患者结肠黏膜中肠杆菌科的丰度增加，同时回肠中吸收ba的转运蛋白减少。与完整回肠患者相比，接受回肠末端切除术的患者结肠中肠杆菌科定植的增加更大，这使我们假设BAs促进了肠杆菌科的肠道定植。人类结肠上皮细胞系暴露于ba可减少线粒体呼吸，增加氧气利用率，并增强几种肠杆菌科成员的上皮粘附性。在公开的人类数据集中，粘膜肠杆菌科与线粒体功能相关基因的表达呈负相关。在小鼠模型中，肠道BA利用率的增加以依赖于细菌呼吸的方式增强了大肠杆菌的定植。总之，我们的研究结果表明，BAs减少了结肠中的线粒体呼吸，导致氧气可用性增加，从而促进肠杆菌科定植。BAs作为宿主-共生相互作用的促进剂的鉴定可能与多种肠道疾病有关。

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引用次数: 0

HIF-2α drives TH2 cells HIF-2α 驱动 TH2 细胞。

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2024-12-17 DOI: 10.1126/scisignal.adv2653

John F. Foley

Inhibiting HIF-2α impairs the development and function of asthma-promoting helper T cells in mice.

抑制HIF-2α可损害小鼠促哮喘辅助性T细胞的发育和功能。

引用次数: 0

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