Science Signaling最新文献

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The host protease KLK5 primes and activates spike proteins to promote human betacoronavirus replication and lung inflammation 宿主蛋白酶 KLK5 可激发和激活尖峰蛋白，促进人类倍他克龙病毒的复制和肺部炎症。

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2024-08-20 DOI: 10.1126/scisignal.adn3785

Hyunjoon Kim, Yeonglim Kang, Semi Kim, Dongbin Park, Seo-Young Heo, Ji-Seung Yoo, Isaac Choi, Monford Paul Abishek N, Jae-Woo Ahn, Jeong-Sun Yang, Nayeon Bak, Kyeong Kyu Kim, Joo-Yeon Lee, Young Ki Choi

Coronaviruses rely on host proteases to activate the viral spike protein, which facilitates fusion with the host cell membrane and the release of viral genomic RNAs into the host cell cytoplasm. The distribution of specific host proteases in the host determines the host, tissue, and cellular tropism of these viruses. Here, we identified the kallikrein (KLK) family member KLK5 as a major host protease secreted by human airway cells and exploited by multiple human betacoronaviruses. KLK5 cleaved both the priming (S1/S2) and activation (S2′) sites of spike proteins from various human betacoronaviruses in vitro. In contrast, KLK12 and KLK13 displayed preferences for either the S2′ or S1/S2 site, respectively. Whereas KLK12 and KLK13 worked in concert to activate SARS-CoV-2 and MERS-CoV spike proteins, KLK5 by itself efficiently activated spike proteins from several human betacoronaviruses, including SARS-CoV-2. Infection of differentiated human bronchial epithelial cells (HBECs) with human betacoronaviruses induced an increase in KLK5 that promoted virus replication. Furthermore, ursolic acid and other related plant-derived triterpenoids that inhibit KLK5 effectively suppressed the replication of SARS-CoV, MERS-CoV, and SARS-CoV-2 in HBECs and mitigated lung inflammation in mice infected with MERS-CoV or SARS-CoV-2. We propose that KLK5 is a pancoronavirus host factor and a promising therapeutic target for current and future coronavirus-induced diseases.

冠状病毒依靠宿主蛋白酶激活病毒尖峰蛋白，从而促进与宿主细胞膜的融合，并将病毒基因组 RNA 释放到宿主细胞的细胞质中。特定宿主蛋白酶在宿主体内的分布决定了这些病毒对宿主、组织和细胞的趋性。在这里，我们确定了kallikrein（KLK）家族成员KLK5是人类气道细胞分泌的一种主要宿主蛋白酶，并被多种人类betacoronaviruses利用。KLK5 在体外可裂解多种人类贝他克隆病毒尖峰蛋白的引物（S1/S2）和激活（S2'）位点。相反，KLK12 和 KLK13 则分别偏好 S2'或 S1/S2 位点。KLK12和KLK13协同激活SARS-CoV-2和MERS-CoV的尖峰蛋白，而KLK5本身则能有效激活包括SARS-CoV-2在内的几种人类betacoronaviruses的尖峰蛋白。分化的人类支气管上皮细胞（HBECs）感染人类betacoronaviruses会诱导KLK5的增加，从而促进病毒的复制。此外，熊果酸和其他相关植物提取的三萜类化合物能抑制 KLK5，它们能有效抑制 SARS-CoV、MERS-CoV 和 SARS-CoV-2 在 HBECs 中的复制，并减轻感染 MERS-CoV 或 SARS-CoV-2 的小鼠的肺部炎症。我们认为 KLK5 是一种胰岛病毒宿主因子，是目前和未来冠状病毒诱发疾病的一个有希望的治疗靶点。

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引用次数: 0

Stroke of DNA DNA 笔触

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2024-08-20 DOI: 10.1126/scisignal.ads4720

Amy E. Baek

Inflammasome activation by circulating DNA leads to recurrent stroke associated with atherosclerosis.

循环 DNA 激活炎症小体导致与动脉粥样硬化相关的中风复发。

引用次数: 0

Hypoxia protects the gut 缺氧保护肠道

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2024-08-13 DOI: 10.1126/scisignal.ads1861

Annalisa M. VanHook

Antibiotic-induced loss of intestinal hypoxia boosts the growth of C. albicans in mice.

抗生素引起的肠道缺氧会促进白僵菌在小鼠体内的生长。

引用次数: 0

Phosphorylation patterns in the AT1R C-terminal tail specify distinct downstream signaling pathways AT1R C 端尾部的磷酸化模式指定了不同的下游信号通路。

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2024-08-13 DOI: 10.1126/scisignal.adk5736

Clarice Gareri, Conrad T. Pfeiffer, Xue Jiang, Joao A. Paulo, Steven P. Gygi, Uyen Pham, Anand Chundi, Laura M. Wingler, Dean P. Staus, Tomasz Maciej Stepniewski, Jana Selent, Emilio Y. Lucero, Alyssa Grogan, Sudarshan Rajagopal, Howard A. Rockman

Different ligands stabilize specific conformations of the angiotensin II type 1 receptor (AT1R) that direct distinct signaling cascades mediated by heterotrimeric G proteins or β-arrestin. These different active conformations are thought to engage distinct intracellular transducers because of differential phosphorylation patterns in the receptor C-terminal tail (the “barcode” hypothesis). Here, we identified the AT1R barcodes for the endogenous agonist AngII, which stimulates both G protein activation and β-arrestin recruitment, and for a synthetic biased agonist that only stimulates β-arrestin recruitment. The endogenous and β-arrestin–biased agonists induced two different ensembles of phosphorylation sites along the C-terminal tail. The phosphorylation of eight serine and threonine residues in the proximal and middle portions of the tail was required for full β-arrestin functionality, whereas phosphorylation of the serine and threonine residues in the distal portion of the tail had little influence on β-arrestin function. Similarly, molecular dynamics simulations showed that the proximal and middle clusters of phosphorylated residues were critical for stable β-arrestin–receptor interactions. These findings demonstrate that ligands that stabilize different receptor conformations induce different phosphorylation clusters in the C-terminal tail as barcodes to evoke distinct receptor-transducer engagement, receptor trafficking, and signaling.

不同的配体会稳定血管紧张素 II 1 型受体（AT1R）的特定构象，从而引导由异源三聚体 G 蛋白或 β-阿司匹林介导的不同信号级联。由于受体 C 端尾部的磷酸化模式不同（"条形码 "假说），这些不同的活性构象被认为与不同的细胞内转导因子有关。在这里，我们确定了同时刺激 G 蛋白活化和 β-restin 募集的内源性激动剂 AngII 和只刺激 β-restin 募集的合成偏激激动剂的 AT1R 条形码。内源性激动剂和β-阿restin偏激激动剂诱导了两种不同的 C 端尾部磷酸化位点组合。尾部近端和中间部分的 8 个丝氨酸和苏氨酸残基的磷酸化是完整的 β-阿restin 功能所必需的，而尾部远端丝氨酸和苏氨酸残基的磷酸化对 β-阿restin的功能影响很小。同样，分子动力学模拟显示，近端和中间的磷酸化残基簇对稳定的 β-restin-受体相互作用至关重要。这些研究结果表明，能稳定不同受体构象的配体会诱导 C 端尾部的不同磷酸化簇作为条形码，从而唤起不同的受体-转换器啮合、受体贩运和信号传导。

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引用次数: 0

Sleep to fight tumors 睡眠对抗肿瘤

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2024-08-06 DOI: 10.1126/scisignal.ads1573

Leslie K. Ferrarelli

Sleep deprivation promotes tumor growth through loss of daily rhythms in cellular lipid metabolism.

睡眠不足会使细胞脂质代谢失去日常节律，从而促进肿瘤生长。

引用次数: 0

Poly-GR repeats associated with ALS/FTD gene C9ORF72 impair translation elongation and induce a ribotoxic stress response in neurons 与 ALS/FTD 基因 C9ORF72 相关的多聚-GR 重复序列会损害神经元的翻译延伸并诱发核糖毒性应激反应。

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2024-08-06 DOI: 10.1126/scisignal.adl1030

Daoyuan Dong, Zhe Zhang, Yini Li, Malgorzata J. Latallo, Shaopeng Wang, Blake Nelson, Rong Wu, Gopinath Krishnan, Fen-Biao Gao, Bin Wu, Shuying Sun

Hexanucleotide repeat expansion in the C9ORF72 gene is the most frequent inherited cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The expansion results in multiple dipeptide repeat proteins, among which arginine-rich poly-GR proteins are highly toxic to neurons and decrease the rate of protein synthesis. We investigated whether the effect on protein synthesis contributes to neuronal dysfunction and degeneration. We found that the expression of poly-GR proteins inhibited global translation by perturbing translation elongation. In iPSC-differentiated neurons, the translation of transcripts with relatively slow elongation rates was further slowed, and stalled, by poly-GR. Elongation stalling increased ribosome collisions and induced a ribotoxic stress response (RSR) mediated by ZAKα that increased the phosphorylation of the kinase p38 and promoted cell death. Knockdown of ZAKα or pharmacological inhibition of p38 ameliorated poly-GR–induced toxicity and improved the survival of iPSC–derived neurons from patients with C9ORF72-ALS/FTD. Our findings suggest that targeting the RSR may be neuroprotective in patients with ALS/FTD caused by repeat expansion in C9ORF72.

C9ORF72 基因的六核苷酸重复扩增是肌萎缩侧索硬化症（ALS）和额颞叶痴呆症（FTD）最常见的遗传病因。这种扩增会产生多种二肽重复蛋白，其中富含精氨酸的多 GR 蛋白对神经元具有很强的毒性，会降低蛋白质的合成速度。我们研究了对蛋白质合成的影响是否会导致神经元功能障碍和退化。我们发现，poly-GR 蛋白的表达通过扰乱翻译延伸抑制了全局翻译。在 iPSC 分化的神经元中，延伸率相对较慢的转录本的翻译在 poly-GR 的作用下进一步减慢和停滞。延伸停滞增加了核糖体碰撞，诱导了由 ZAKα 介导的核糖毒性应激反应（RSR），该反应增加了激酶 p38 的磷酸化，促进了细胞死亡。敲除 ZAKα 或药物抑制 p38 可改善聚-GR 诱导的毒性，并提高 C9ORF72-ALS/FTD 患者 iPSC 衍生神经元的存活率。我们的研究结果表明，靶向 RSR 可能对 C9ORF72 重复扩增引起的 ALS/FTD 患者具有神经保护作用。

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引用次数: 0

The dopaminergic system promotes neprilysin-mediated degradation of amyloid-β in the brain 多巴胺能系统促进了大脑中肾素介导的淀粉样蛋白-β降解。

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2024-08-06 DOI: 10.1126/scisignal.adk1822

Naoto Watamura, Naomasa Kakiya, Ryo Fujioka, Naoko Kamano, Mika Takahashi, Per Nilsson, Takashi Saito, Nobuhisa Iwata, Shigeyoshi Fujisawa, Takaomi C. Saido

Deposition of amyloid-β (Aβ) in the brain can impair neuronal function and contribute to cognitive decline in Alzheimer’s disease (AD). Here, we found that dopamine and the dopamine precursor levodopa (also called l-DOPA) induced Aβ degradation in the brain. Chemogenetic approaches in mice revealed that the activation of dopamine release from ventral tegmental area (VTA) neurons increased the abundance and activity of the Aβ-degrading enzyme neprilysin and reduced the amount of Aβ deposits in the prefrontal cortex in a neprilysin-dependent manner. Aged mice had less dopamine and neprilysin in the anterior cortex, a decrease that was accentuated in AD model mice. Treating AD model mice with levodopa reduced Aβ deposition and improved cognitive function. These observations demonstrate that dopamine promotes brain region–specific, neprilysin-dependent degradation of Aβ, suggesting that dopamine-associated strategies have the potential to treat this aspect of AD pathology.

淀粉样蛋白-β（Aβ）在大脑中的沉积会损害神经元功能，导致阿尔茨海默病（AD）患者认知能力下降。在这里，我们发现多巴胺和多巴胺前体左旋多巴（又称 l-DOPA）能诱导大脑中 Aβ 的降解。小鼠的化学遗传学方法显示，激活腹侧被盖区（VTA）神经元的多巴胺释放会增加Aβ降解酶肾小球酶的丰度和活性，并以肾小球酶依赖的方式减少前额叶皮质中Aβ的沉积量。老龄小鼠前额皮质中的多巴胺和胰蛋白酶含量较少，这种减少在AD模型小鼠中更为明显。用左旋多巴治疗AD模型小鼠可减少Aβ沉积并改善认知功能。这些观察结果表明，多巴胺能促进脑区特异性的、依赖肾素酶的Aβ降解，这表明与多巴胺相关的策略有可能治疗AD病理学的这一方面。

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引用次数: 0

Enhancing naloxone 加强纳洛酮。

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2024-07-30 DOI: 10.1126/scisignal.adr9944

John F. Foley

A negative allosteric modulator of the μ-opioid receptor enhances the efficacy of naloxone.

μ-阿片受体的负异构调节剂可增强纳洛酮的药效。

引用次数: 0

The kinase ITK controls a Ca2+-mediated switch that balances TH17 and Treg cell differentiation 激酶 ITK 可控制 Ca2+ 介导的开关，从而平衡 TH17 和 Treg 细胞的分化。

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2024-07-23 DOI: 10.1126/scisignal.adh2381

Orchi Anannya, Weishan Huang, Avery August

The balance of proinflammatory T helper type 17 (T_H17) and anti-inflammatory T regulatory (T_reg) cells is crucial for immune homeostasis in health and disease. The differentiation of naïve CD4⁺ T cells into T_H17 and T_reg cells depends on T cell receptor (TCR) signaling mediated, in part, by interleukin-2–inducible T cell kinase (ITK), which stimulates mitogen-activated protein kinases (MAPKs) and Ca²⁺ signaling. Here, we report that, in the absence of ITK activity, naïve murine CD4⁺ T cells cultured under T_H17-inducing conditions expressed the T_reg transcription factor Foxp3 and did not develop into T_H17 cells. Furthermore, ITK inhibition in vivo during allergic inflammation increased the T_reg:T_H17 ratio in the lung. These switched Foxp3⁺ T_reg-like cells had suppressive function, and their transcriptomic profile resembled that of differentiated, induced T_reg (iT_reg) cells, but their chromatin accessibility profiles were intermediate between T_H17 and iT_reg cells. Like iT_reg cells, switched Foxp3⁺ T_reg-like cells had reductions in the expression of genes involved in mitochondrial oxidative phosphorylation and glycolysis, in the activation of the mechanistic target of rapamycin (mTOR) signaling pathway, and in the abundance of the T_H17 pioneer transcription factor BATF. This ITK-dependent switch between T_H17 and T_reg cells depended on Ca²⁺ signaling but not on MAPKs. These findings suggest potential strategies for fine-tuning TCR signal strength through ITK to control the balance of T_H17 and T_reg cells.

促炎 T 辅助细胞 17 型（TH17）和抗炎 T 调节细胞（Treg）的平衡对健康和疾病中的免疫平衡至关重要。幼稚 CD4+ T 细胞向 TH17 和 Treg 细胞的分化依赖于 T 细胞受体（TCR）信号传导，部分由白细胞介素-2 诱导的 T 细胞激酶（ITK）介导，ITK 刺激丝裂原活化蛋白激酶（MAPKs）和 Ca2+ 信号传导。在这里，我们报告了在 ITK 活性缺失的情况下，在 TH17 诱导条件下培养的小鼠幼稚 CD4+ T 细胞会表达 Treg 转录因子 Foxp3，并且不会发育成 TH17 细胞。此外，在体内过敏性炎症期间抑制 ITK 会增加肺中 Treg 与 TH17 的比例。这些切换的Foxp3+ Treg样细胞具有抑制功能，它们的转录组特征与分化的诱导Treg（iTreg）细胞相似，但它们的染色质可及性特征介于TH17和iTreg细胞之间。与 iTreg 细胞一样，切换后的 Foxp3+ Treg 样细胞也减少了参与线粒体氧化磷酸化和糖酵解的基因的表达、雷帕霉素机械靶标（mTOR）信号通路的激活以及 TH17 先驱转录因子 BATF 的丰度。这种 ITK 依赖性的 TH17 和 Treg 细胞之间的切换取决于 Ca2+ 信号，而不是 MAPK。这些发现提示了通过 ITK 微调 TCR 信号强度以控制 TH17 和 Treg 细胞平衡的潜在策略。

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引用次数: 0

Generation of antitumor chimeric antigen receptors incorporating T cell signaling motifs 生成含有 T 细胞信号基团的抗肿瘤嵌合抗原受体。

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2024-07-23 DOI: 10.1126/scisignal.adp8569

Lakshmi Balagopalan, Taylor Moreno, Haiying Qin, Benjamin C. Angeles, Taisuke Kondo, Jason Yi, Katherine M. McIntire, Neriah Alvinez, Sandeep Pallikkuth, Mariah E. Lee, Hidehiro Yamane, Andy D. Tran, Philippe Youkharibache, Raul E. Cachau, Naomi Taylor, Lawrence E. Samelson

Chimeric antigen receptor (CAR) T cells have been used to successfully treat various blood cancers, but adverse effects have limited their potential. Here, we developed chimeric adaptor proteins (CAPs) and CAR tyrosine kinases (CAR-TKs) in which the intracellular ζ T cell receptor (TCRζ) chain was replaced with intracellular protein domains to stimulate signaling downstream of the TCRζ chain. CAPs contain adaptor domains and the kinase domain of ZAP70, whereas CAR-TKs contain only ZAP70 domains. We hypothesized that CAPs and CAR-TKs would be more potent than CARs because they would bypass both the steps that define the signaling threshold of TCRζ and the inhibitory regulation of upstream molecules. CAPs were too potent and exhibited high tonic signaling in vitro. In contrast, CAR-TKs exhibited high antitumor efficacy and significantly enhanced long-term tumor clearance in leukemia-bearing NSG mice as compared with the conventional CD19-28ζ-CAR-T cells. CAR-TKs were activated in a manner independent of the kinase Lck and displayed slower phosphorylation kinetics and prolonged signaling compared with the 28ζ-CAR. Lck inhibition attenuated CAR-TK cell exhaustion and improved long-term function. The distinct signaling properties of CAR-TKs may therefore be harnessed to improve the in vivo efficacy of T cells engineered to express an antitumor chimeric receptor.

嵌合抗原受体（CAR）T细胞已被成功用于治疗各种血癌，但不良反应限制了其潜力。在这里，我们开发了嵌合适配蛋白（CAPs）和CAR酪氨酸激酶（CAR-TKs），其中细胞内的ζT细胞受体（TCRζ）链被细胞内蛋白结构域取代，以刺激TCRζ链下游的信号传导。CAPs含有适配器结构域和ZAP70的激酶结构域，而CAR-TKs只含有ZAP70结构域。我们假设，CAPs 和 CAR-TKs 比 CARs 更有效，因为它们可以绕过确定 TCRζ 信号阈值的步骤和上游分子的抑制调节。CAP的效力太强，在体外表现出高强直性信号。相比之下，与传统的CD19-28ζ-CAR-T细胞相比，CAR-TK在白血病NSG小鼠体内表现出很高的抗肿瘤效力，并显著提高了长期肿瘤清除率。CAR-TK 的激活方式与激酶 Lck 无关，与 28ζ-CAR 相比，其磷酸化动力学更慢，信号传导时间更长。抑制 Lck 可减轻 CAR-TK 细胞的衰竭并改善其长期功能。因此，可以利用CAR-TK不同的信号特性来提高表达抗肿瘤嵌合受体的T细胞的体内疗效。

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