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TNF-α signals through ITK-Akt-mTOR to drive CD4+ T cell metabolic reprogramming, which is dysregulated in rheumatoid arthritis TNF-α 通过 ITK-Akt-mTOR 信号驱动 CD4+ T 细胞代谢重编程，类风湿性关节炎患者的代谢重编程失调

IF 7.3 1区生物学 Q1 Biochemistry, Genetics and Molecular Biology

Science Signaling

Pub Date : 2024-04-23 DOI: 10.1126/scisignal.adg5678

Emma L. Bishop, Nancy Gudgeon, Taylor Fulton-Ward, Victoria Stavrou, Jennie Roberts, Adam Boufersaoui, Daniel A. Tennant, Martin Hewison, Karim Raza, Sarah Dimeloe

Upon activation, T cells undergo metabolic reprogramming to meet the bioenergetic demands of clonal expansion and effector function. Because dysregulated T cell cytokine production and metabolic phenotypes coexist in chronic inflammatory disease, including rheumatoid arthritis (RA), we investigated whether inflammatory cytokines released by differentiating T cells amplified their metabolic changes. We found that tumor necrosis factor–α (TNF-α) released by human naïve CD4⁺ T cells upon activation stimulated the expression of a metabolic transcriptome and increased glycolysis, amino acid uptake, mitochondrial oxidation of glutamine, and mitochondrial biogenesis. The effects of TNF-α were mediated by activation of Akt-mTOR signaling by the kinase ITK and did not require the NF-κB pathway. TNF-α stimulated the differentiation of naïve cells into proinflammatory T helper 1 (T_H1) and T_H17 cells, but not that of regulatory T cells. CD4⁺ T cells from patients with RA showed increased TNF-α production and consequent Akt phosphorylation upon activation. These cells also exhibited increased mitochondrial mass, particularly within proinflammatory T cell subsets implicated in disease. Together, these findings suggest that T cell–derived TNF-α drives their metabolic reprogramming by promoting signaling through ITK, Akt, and mTOR, which is dysregulated in autoinflammatory disease.

激活后，T 细胞会进行新陈代谢重编程，以满足克隆扩增和效应功能的生物能需求。由于慢性炎症性疾病（包括类风湿性关节炎）中同时存在T细胞细胞因子分泌失调和代谢表型，我们研究了分化T细胞释放的炎性细胞因子是否会扩大其代谢变化。我们发现，人类幼稚 CD4+ T 细胞激活后释放的肿瘤坏死因子-α（TNF-α）刺激了代谢转录组的表达，并增加了糖酵解、氨基酸摄取、谷氨酰胺的线粒体氧化和线粒体生物生成。TNF-α 的作用由激酶 ITK 激活 Akt-mTOR 信号介导，不需要 NF-κB 途径。TNF-α能刺激幼稚细胞分化为促炎性T辅助细胞1（TH1）和TH17细胞，但不能刺激调节性T细胞的分化。红斑狼疮患者的 CD4+ T 细胞在激活后显示 TNF-α 生成增加，Akt 磷酸化也随之增加。这些细胞还表现出线粒体质量增加，尤其是在与疾病有关的促炎 T 细胞亚群中。这些发现共同表明，T细胞衍生的TNF-α通过促进ITK、Akt和mTOR的信号转导来驱动其代谢重编程，而这在自身炎症性疾病中是失调的。

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引用次数: 0

Glia are powerhouses for sleep 神经胶质细胞是睡眠的动力源泉

IF 7.3 1区生物学 Q1 Biochemistry, Genetics and Molecular Biology

Science Signaling

Pub Date : 2024-04-23 DOI: 10.1126/scisignal.adp9115

Leslie K. Ferrarelli

Glia take up and detoxify neurotoxic lipids on a wake-sleep cycle, in turn promoting healthy sleep.

胶质细胞在唤醒-睡眠周期中吸收并解毒神经毒性脂质，进而促进健康睡眠。

引用次数: 0

Optogenetically controlled inflammasome activation demonstrates two phases of cell swelling during pyroptosis 光遗传学控制的炎症小体激活显示了热核病过程中细胞肿胀的两个阶段

IF 7.3 1区生物学 Q1 Biochemistry, Genetics and Molecular Biology

Science Signaling

Pub Date : 2024-04-23 DOI: 10.1126/scisignal.abn8003

Julien Nadjar, Sylvain Monnier, Estelle Bastien, Anne-Laure Huber, Christiane Oddou, Léa Bardoulet, Hubert B. Leloup, Gabriel Ichim, Christophe Vanbelle, Bénédicte F. Py, Olivier Destaing, Virginie Petrilli

Inflammasomes are multiprotein platforms that control caspase-1 activation, which process the inactive precursor forms of the inflammatory cytokines IL-1β and IL-18, leading to an inflammatory type of programmed cell death called pyroptosis. Studying inflammasome-driven processes, such as pyroptosis-induced cell swelling, under controlled conditions remains challenging because the signals that activate pyroptosis also stimulate other signaling pathways. We designed an optogenetic approach using a photo-oligomerizable inflammasome core adapter protein, apoptosis-associated speck–like containing a caspase recruitment domain (ASC), to temporally and quantitatively manipulate inflammasome activation. We demonstrated that inducing the light-sensitive oligomerization of ASC was sufficient to recapitulate the classical features of inflammasomes within minutes. This system showed that there were two phases of cell swelling during pyroptosis. This approach offers avenues for biophysical investigations into the intricate nature of cellular volume control and plasma membrane rupture during cell death.

炎症体是控制 caspase-1 激活的多蛋白平台，可处理炎症细胞因子 IL-1β 和 IL-18 的非活性前体形式，从而导致一种炎症性的程序性细胞死亡，即所谓的 "裂解热"。在受控条件下研究炎性体驱动的过程，如热休克诱导的细胞肿胀，仍然具有挑战性，因为激活热休克的信号也会刺激其他信号通路。我们设计了一种光遗传学方法，利用可光配体化的炎症小体核心适配蛋白--含有卡巴酶招募结构域的凋亡相关类斑点（ASC）来定时、定量地操纵炎症小体的激活。我们证明，诱导 ASC 的光敏寡聚足以在几分钟内重现炎症小体的经典特征。该系统显示，在热蛋白沉积过程中，细胞肿胀分为两个阶段。这种方法为生物物理研究细胞死亡过程中细胞体积控制和质膜破裂的复杂性质提供了途径。

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引用次数: 0

EGFR-dependent endocytosis of Wnt9a and Fzd9b promotes β-catenin signaling during hematopoietic stem cell development in zebrafish 在斑马鱼造血干细胞发育过程中，表皮生长因子受体依赖性内吞 Wnt9a 和 Fzd9b，促进β-catenin 信号传导

IF 7.3 1区生物学 Q1 Biochemistry, Genetics and Molecular Biology

Science Signaling

Pub Date : 2024-04-16 DOI: 10.1126/scisignal.adf4299

Nicole Nguyen, Kelsey A. Carpenter, Jessica Ensing, Carla Gilliland, Emma J. Rudisel, Emily M. Mu, Kate E. Thurlow, Timothy J. Triche Jr., Stephanie Grainger

Cell-to-cell communication through secreted Wnt ligands that bind to members of the Frizzled (Fzd) family of transmembrane receptors is critical for development and homeostasis. Wnt9a signals through Fzd9b, the co-receptor LRP5 or LRP6 (LRP5/6), and the epidermal growth factor receptor (EGFR) to promote early proliferation of zebrafish and human hematopoietic stem cells during development. Here, we developed fluorescently labeled, biologically active Wnt9a and Fzd9b fusion proteins to demonstrate that EGFR-dependent endocytosis of the ligand-receptor complex was required for signaling. In human cells, the Wnt9a-Fzd9b complex was rapidly endocytosed and trafficked through early and late endosomes, lysosomes, and the endoplasmic reticulum. Using small-molecule inhibitors and genetic and knockdown approaches, we found that Wnt9a-Fzd9b endocytosis required EGFR-mediated phosphorylation of the Fzd9b tail, caveolin, and the scaffolding protein EGFR protein substrate 15 (EPS15). LRP5/6 and the downstream signaling component AXIN were required for Wnt9a-Fzd9b signaling but not for endocytosis. Knockdown or loss of EPS15 impaired hematopoietic stem cell development in zebrafish. Other Wnt ligands do not require endocytosis for signaling activity, implying that specific modes of endocytosis and trafficking may represent a method by which Wnt-Fzd specificity is established.

通过与 Frizzled（Fzd）跨膜受体家族成员结合的分泌型 Wnt 配体进行的细胞间通讯对发育和稳态至关重要。Wnt9a通过Fzd9b、共受体LRP5或LRP6（LRP5/6）以及表皮生长因子受体（EGFR）发出信号，在发育过程中促进斑马鱼和人类造血干细胞的早期增殖。在这里，我们开发了荧光标记的、具有生物活性的Wnt9a和Fzd9b融合蛋白，证明配体-受体复合物的信号传导需要表皮生长因子受体依赖性内吞作用。在人体细胞中，Wnt9a-Fzd9b复合物被快速内吞并通过早期和晚期内体、溶酶体和内质网运输。利用小分子抑制剂和基因敲除方法，我们发现 Wnt9a-Fzd9b 的内吞需要表皮生长因子受体介导的 Fzd9b 尾部、洞穴素和支架蛋白表皮生长因子受体蛋白底物 15（EPS15）的磷酸化。Wnt9a-Fzd9b信号转导需要LRP5/6和下游信号转导成分AXIN，但内吞却不需要。EPS15的敲除或缺失会影响斑马鱼造血干细胞的发育。其他Wnt配体的信号活动不需要内吞，这意味着特定的内吞和转运模式可能是建立Wnt-Fzd特异性的一种方法。

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引用次数: 0

Taking down tumors takes atypical integrins 攻克肿瘤需要非典型整合素

IF 7.3 1区生物学 Q1 Biochemistry, Genetics and Molecular Biology

Science Signaling

Pub Date : 2024-04-16 DOI: 10.1126/scisignal.adp7684

John F. Foley

An unexpected integrin pairing enhances T cell receptor signaling and cytotoxicity in antitumor T cells.

一种意想不到的整合素配对可增强抗肿瘤 T 细胞的 T 细胞受体信号转导和细胞毒性。

引用次数: 0

Decoding cocaine-induced proteomic adaptations in the mouse nucleus accumbens 解码可卡因诱导的小鼠脑核蛋白质组适应性变化

IF 7.3 1区生物学 Q1 Biochemistry, Genetics and Molecular Biology

Science Signaling

Pub Date : 2024-04-16 DOI: 10.1126/scisignal.adl4738

Philipp Mews, Lucas Sosnick, Ashik Gurung, Simone Sidoli, Eric J. Nestler

Cocaine use disorder (CUD) is a chronic neuropsychiatric condition that results from enduring cellular and molecular adaptations. Among substance use disorders, CUD is notable for its rising prevalence and the lack of approved pharmacotherapies. The nucleus accumbens (NAc), a region that is integral to the brain’s reward circuitry, plays a crucial role in the initiation and continuation of maladaptive behaviors that are intrinsic to CUD. Leveraging advancements in neuroproteomics, we undertook a proteomic analysis that spanned membrane, cytosolic, nuclear, and chromatin compartments of the NAc in a mouse model. The results unveiled immediate and sustained proteomic modifications after cocaine exposure and during prolonged withdrawal. We identified congruent protein regulatory patterns during initial cocaine exposure and reexposure after withdrawal, which contrasted with distinct patterns during withdrawal. Pronounced proteomic shifts within the membrane compartment indicated adaptive and long-lasting molecular responses prompted by cocaine withdrawal. In addition, we identified potential protein translocation events between soluble-nuclear and chromatin-bound compartments, thus providing insight into intracellular protein dynamics after cocaine exposure. Together, our findings illuminate the intricate proteomic landscape that is altered in the NAc by cocaine use and provide a dataset for future research toward potential therapeutics.

可卡因使用障碍（CUD）是一种慢性神经精神疾病，由持久的细胞和分子适应引起。在药物使用失调症中，可卡因使用失调症因其发病率不断上升和缺乏经批准的药物疗法而备受关注。作为大脑奖赏回路中不可或缺的一个区域--伏隔核（NAc），在 CUD 所固有的适应不良行为的开始和持续中起着至关重要的作用。利用神经保护组学的进步，我们对小鼠模型的 NAc 进行了蛋白质组分析，分析范围包括膜、细胞质、核和染色质。结果揭示了暴露于可卡因后和长期戒断过程中即时和持续的蛋白质组学改变。我们确定了在初次接触可卡因和戒断后再次接触可卡因期间相同的蛋白质调控模式，这与戒断期间不同的模式形成了鲜明对比。膜区内明显的蛋白质组变化表明可卡因戒断引起了适应性和持久的分子反应。此外，我们还发现了可溶性-核区和染色质结合区之间潜在的蛋白质转位事件，从而深入了解了暴露于可卡因后细胞内蛋白质的动态变化。总之，我们的研究结果阐明了使用可卡因会改变 NAc 中错综复杂的蛋白质组景观，并为未来研究潜在疗法提供了数据集。

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引用次数: 0

Miz1 represses type I interferon production and limits viral clearance during influenza A virus infection Miz1 在甲型流感病毒感染过程中抑制 I 型干扰素的产生并限制病毒的清除

IF 7.3 1区生物学 Q1 Biochemistry, Genetics and Molecular Biology

Science Signaling

Pub Date : 2024-04-09 DOI: 10.1126/scisignal.adg7867

Wenjiao Wu, Vinothini Arunagiri, Hanh Chi Do-Umehara, Cong Chen, Shuyin Gu, Indrani Biswas, Karen M. Ridge, G. R. Scott Budinger, Shuwen Liu, Jing Liu

Type I interferons (IFNs) are critical for the antiviral immune response, and fine-tuning type I IFN production is critical to effectively clearing viruses without causing harmful immunopathology. We showed that the transcription factor Miz1 epigenetically repressed the expression of genes encoding type I IFNs in mouse lung epithelial cells by recruiting histone deacetylase 1 (HDAC1) to the promoters of Ifna and Ifnb. Loss of function of Miz1 resulted in augmented production of these type I IFNs during influenza A virus (IAV) infection, leading to improved viral clearance in vitro and in vivo. IAV infection induced Miz1 accumulation by promoting the cullin-4B (CUL4B)–mediated ubiquitylation and degradation of the E3 ubiquitin ligase Mule (Mcl-1 ubiquitin ligase E3; also known as Huwe1 or Arf-BP1), which targets Miz1 for degradation. As a result, Miz1 accumulation limited type I IFN production and favored viral replication. This study reveals a previously unrecognized function of Miz1 in regulating antiviral defense and a potential mechanism for influenza viruses to evade host immune defense.

I型干扰素（IFN）是抗病毒免疫反应的关键，而微调I型干扰素的产生对有效清除病毒而不引起有害的免疫病理至关重要。我们发现，转录因子Miz1通过招募组蛋白去乙酰化酶1（HDAC1）到Ifna和Ifnb的启动子上，对小鼠肺上皮细胞中编码I型IFN的基因的表达进行表观遗传学抑制。在甲型流感病毒（IAV）感染期间，Miz1的功能缺失会导致这些I型IFNs的产生增加，从而提高体外和体内的病毒清除率。IAV 感染通过促进 Cullin-4B (CUL4B) 介导的泛素化和 E3 泛素连接酶 Mule（Mcl-1 泛素连接酶 E3；又称 Huwe1 或 Arf-BP1）的降解来诱导 Miz1 的积累，而 Mule 是 Miz1 的降解靶标。因此，Miz1 的积累限制了 I 型 IFN 的产生，有利于病毒的复制。这项研究揭示了 Miz1 在调节抗病毒防御中一种以前未被发现的功能，以及流感病毒逃避宿主免疫防御的一种潜在机制。

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引用次数: 0

Sensing stretch to suppress appetite 感知伸展以抑制食欲

IF 7.3 1区生物学 Q1 Biochemistry, Genetics and Molecular Biology

Science Signaling

Pub Date : 2024-04-09 DOI: 10.1126/scisignal.adp6031

Wei Wong

Food intake activates a mechanosensitive ion channel that inhibits ghrelin production and reduces appetite.

食物摄入会激活机械敏感性离子通道，从而抑制胃泌素的分泌并降低食欲。

引用次数: 0

Blocking lipid synthesis induces DNA damage in prostate cancer and increases cell death caused by PARP inhibition 阻止脂质合成会诱发前列腺癌的 DNA 损伤，并增加 PARP 抑制造成的细胞死亡

IF 7.3 1区生物学 Q1 Biochemistry, Genetics and Molecular Biology

Science Signaling

Pub Date : 2024-04-09 DOI: 10.1126/scisignal.adh1922

Caroline Fidalgo Ribeiro, Silvia Rodrigues, Debora Campanella Bastos, Giuseppe Nicolò Fanelli, Hubert Pakula, Marco Foiani, Giorgia Zadra, Massimo Loda

Androgen deprivation therapy (ADT) is the primary treatment for prostate cancer; however, resistance to ADT invariably develops, leading to castration-resistant prostate cancer (CRPC). Prostate cancer progression is marked by increased de novo synthesis of fatty acids due to overexpression of fatty acid synthase (FASN), making this enzyme a therapeutic target for prostate cancer. Inhibition of FASN results in increased intracellular amounts of ceramides and sphingomyelin, leading to DNA damage through the formation of DNA double-strand breaks and cell death. We found that combining a FASNi with the poly-ADP ribose polymerase (PARP) inhibitor olaparib, which induces cell death by blocking DNA damage repair, resulted in a more pronounced reduction in cell growth than that caused by either drug alone. Human CRPC organoids treated with a combination of PARP and FASNi were smaller, had decreased cell proliferation, and showed increased apoptosis and necrosis. Together, these data indicate that targeting FASN increases the therapeutic efficacy of PARP inhibitors by impairing DNA damage repair, suggesting that combination therapies should be explored for CRPC.

雄激素剥夺疗法（ADT）是治疗前列腺癌的主要方法；然而，ADT总会产生耐药性，导致阉割耐药前列腺癌（CRPC）。由于脂肪酸合成酶（FASN）的过度表达，脂肪酸的从头合成增加，从而使这种酶成为前列腺癌的治疗靶点。抑制 FASN 会导致细胞内神经酰胺和鞘磷脂的含量增加，从而形成 DNA 双链断裂，导致 DNA 损伤和细胞死亡。我们发现，将 FASNi 与聚-ADP 核糖聚合酶（PARP）抑制剂奥拉帕利（奥拉帕利通过阻断 DNA 损伤修复诱导细胞死亡）结合使用，会比单独使用其中一种药物更明显地减少细胞生长。用PARP和FASNi联合治疗的人类CRPC器官组织体积更小，细胞增殖减少，细胞凋亡和坏死增加。这些数据共同表明，以FASN为靶点会损害DNA损伤修复，从而提高PARP抑制剂的疗效，这表明应该探索CRPC的联合疗法。

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引用次数: 0

The heavy subunit of ferritin stimulates NLRP3 inflammasomes in hepatic stellate cells through ICAM-1 to drive hepatic inflammation 铁蛋白重亚基通过 ICAM-1 刺激肝星状细胞中的 NLRP3 炎症小体，从而驱动肝脏炎症

IF 7.3 1区生物学 Q1 Biochemistry, Genetics and Molecular Biology

Science Signaling

Pub Date : 2024-04-02 DOI: 10.1126/scisignal.ade4335

Manuel A. Fernandez-Rojo, Michael A. Pearen, Anita G. Burgess, Maria P. Ikonomopoulou, Diem Hoang-Le, Berit Genz, Silvia L. Saggiomo, Sujeevi S. K. Nawaratna, Maura Poli, Regina Reissmann, Geoffrey N. Gobert, Urban Deutsch, Britta Engelhardt, Andrew J. Brooks, Alun Jones, Paolo Arosio, Grant A. Ramm

Serum ferritin concentrations increase during hepatic inflammation and correlate with the severity of chronic liver disease. Here, we report a molecular mechanism whereby the heavy subunit of ferritin (FTH) contributes to hepatic inflammation. We found that FTH induced activation of the NLRP3 inflammasome and secretion of the proinflammatory cytokine interleukin-1β (IL-1β) in primary rat hepatic stellate cells (HSCs) through intercellular adhesion molecule–1 (ICAM-1). FTH–ICAM-1 stimulated the expression of Il1b, NLRP3 inflammasome activation, and the processing and secretion of IL-1β in a manner that depended on plasma membrane remodeling, clathrin-mediated endocytosis, and lysosomal destabilization. FTH–ICAM-1 signaling at early endosomes stimulated Il1b expression, implying that this endosomal signaling primed inflammasome activation in HSCs. In contrast, lysosomal destabilization was required for FTH-induced IL-1β secretion, suggesting that lysosomal damage activated inflammasomes. FTH induced IL-1β production in liver slices from wild-type mice but not in those from Icam1^−/− or Nlrp3^−/− mice. Thus, FTH signals through its receptor ICAM-1 on HSCs to activate the NLRP3 inflammasome. We speculate that this pathway contributes to hepatic inflammation, a key process that stimulates hepatic fibrogenesis associated with chronic liver disease.

肝脏炎症时血清铁蛋白浓度会升高，并与慢性肝病的严重程度相关。在这里，我们报告了铁蛋白重亚基（FTH）促进肝脏炎症的分子机制。我们发现 FTH 通过细胞间粘附分子-1（ICAM-1）诱导原代大鼠肝星状细胞（HSCs）激活 NLRP3 炎性体并分泌促炎细胞因子白细胞介素-1β（IL-1β）。FTH-ICAM-1刺激了Il1b的表达、NLRP3炎性体的激活以及IL-1β的加工和分泌，其方式依赖于质膜重塑、凝胶酶介导的内吞和溶酶体失稳。早期内体的FTH-ICAM-1信号刺激了Il1b的表达，这意味着这种内体信号激活了造血干细胞中的炎性体。相反，溶酶体失稳是FTH诱导IL-1β分泌的必要条件，这表明溶酶体损伤激活了炎性体。FTH能诱导野生型小鼠肝切片产生IL-1β，但不能诱导Icam1-/-或Nlrp3-/-小鼠肝切片产生IL-1β。因此，FTH通过造血干细胞上的受体ICAM-1发出信号，激活NLRP3炎性体。我们推测这一途径有助于肝脏炎症，而肝脏炎症是刺激与慢性肝病相关的肝纤维化的关键过程。

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