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CD98hc promotes drug resistance in extranodal natural killer/T cell lymphoma through tumor cell–derived small extracellular vesicles CD98hc 通过肿瘤细胞衍生的细胞外小泡促进结节外自然杀伤/T 细胞淋巴瘤的耐药性
IF 6.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-10 DOI: 10.1126/scisignal.adf9388
Liming Liao, Ping Yang, Weilong Zhang, Shuyu Yu, Hongmei Jing, Xiaofeng Zheng
Extranodal natural killer/T cell lymphoma (ENKTL) shows a high rate of recurrence after chemoradiotherapy. Drug resistance can be mediated by the cargo of small extracellular vesicles (sEVs). Here, we show that high abundance of the transmembrane glycoprotein CD98hc in tumor cells and serum sEVs was associated with ENKTL progression and drug resistance. Mechanistically, PEGylated-asparaginase (PEG-asp) treatment, a common therapy against ENKTL, promoted the translocation of the transcription factor ATF4 to the nucleus, where it was stabilized by USP1 and subsequently increased CD98hc expression. CD98hc delivered in tumor cell–derived sEVs increased tumor cell proliferation and drug resistance in a cultured human NK lymphoma cell line, animal models, and samples from patients with refractory/relapse ENKTL. Moreover, inhibiting both USP1 and EV secretion synergistically enhanced the cytotoxicity of PEG-asp. These data suggest that targeting CD98hc in the treatment of ENKTL may be beneficial in overcoming drug resistance.
结节外自然杀伤/T细胞淋巴瘤(ENKTL)在化疗放疗后复发率很高。耐药性可能是由细胞外小泡(sEVs)的载体介导的。在这里,我们发现肿瘤细胞和血清 sEVs 中跨膜糖蛋白 CD98hc 的高丰度与 ENKTL 的进展和耐药性有关。从机理上讲,PEG化天冬酰胺酶(PEG-asp)是治疗ENKTL的一种常用疗法,它能促进转录因子ATF4转位到细胞核,并在细胞核中被USP1稳定,从而增加CD98hc的表达。在培养的人类 NK 淋巴瘤细胞系、动物模型和难治/复发 ENKTL 患者样本中,肿瘤细胞衍生的 sEVs 中的 CD98hc 增加了肿瘤细胞的增殖和耐药性。此外,抑制 USP1 和 EV 分泌可协同增强 PEG-asp 的细胞毒性。这些数据表明,靶向 CD98hc 治疗 ENKTL 可能有利于克服耐药性。
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引用次数: 0
Signal flow in the NMDA receptor–dependent phosphoproteome regulates postsynaptic plasticity for aversive learning 依赖于 NMDA 受体的磷酸蛋白体的信号流调节突触后的可塑性,从而促进厌恶性学习
IF 6.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-10 DOI: 10.1126/scisignal.ado9852
Yasuhiro Funahashi, Rijwan Uddin Ahammad, Xinjian Zhang, Emran Hossen, Masahiro Kawatani, Shinichi Nakamuta, Akira Yoshimi, Minhua Wu, Huanhuan Wang, Mengya Wu, Xu Li, Md Omar Faruk, Md Hasanuzzaman Shohag, You-Hsin Lin, Daisuke Tsuboi, Tomoki Nishioka, Keisuke Kuroda, Mutsuki Amano, Yukihiko Noda, Kiyofumi Yamada, Kenji Sakimura, Taku Nagai, Takayuki Yamashita, Shigeo Uchino, Kozo Kaibuchi
Structural plasticity of dendritic spines in the nucleus accumbens (NAc) is crucial for learning from aversive experiences. Activation of NMDA receptors (NMDARs) stimulates Ca2+-dependent signaling that leads to changes in the actin cytoskeleton, mediated by the Rho family of GTPases, resulting in postsynaptic remodeling essential for learning. We investigated how phosphorylation events downstream of NMDAR activation drive the changes in synaptic morphology that underlie aversive learning. Large-scale phosphoproteomic analyses of protein kinase targets in mouse striatal/accumbal slices revealed that NMDAR activation resulted in the phosphorylation of 194 proteins, including RhoA regulators such as ARHGEF2 and ARHGAP21. Phosphorylation of ARHGEF2 by the Ca2+-dependent protein kinase CaMKII enhanced its RhoGEF activity, thereby activating RhoA and its downstream effector Rho-associated kinase (ROCK/Rho-kinase). Further phosphoproteomic analysis identified 221 ROCK targets, including the postsynaptic scaffolding protein SHANK3, which is crucial for its interaction with NMDARs and other postsynaptic scaffolding proteins. ROCK-mediated phosphorylation of SHANK3 in the NAc was essential for spine growth and aversive learning. These findings demonstrate that NMDAR activation initiates a phosphorylation cascade crucial for learning and memory.
脑内凹凸核(NAc)树突棘的结构可塑性对于从厌恶经验中学习至关重要。NMDA 受体(NMDAR)的激活会刺激 Ca2+ 依赖性信号传导,从而导致肌动蛋白细胞骨架在 Rho 系列 GTP 酶的介导下发生变化,导致对学习至关重要的突触后重塑。我们研究了 NMDAR 激活下游的磷酸化事件如何驱动突触形态的变化,而突触形态的变化是厌恶性学习的基础。对小鼠纹状体/丘脑切片中的蛋白激酶靶点进行的大规模磷酸化蛋白质组学分析表明,NMDAR 的激活导致了 194 种蛋白质的磷酸化,其中包括 RhoA 调控因子,如 ARHGEF2 和 ARHGAP21。钙离子依赖性蛋白激酶 CaMKII 对 ARHGEF2 的磷酸化增强了其 RhoGEF 活性,从而激活了 RhoA 及其下游效应物 Rho-associated 激酶(ROCK/Rho-激酶)。进一步的磷酸化蛋白组学分析确定了 221 个 ROCK 靶点,包括突触后支架蛋白 SHANK3,该蛋白对 ROCK 与 NMDAR 及其他突触后支架蛋白的相互作用至关重要。ROCK 介导的 SHANK3 在 NAc 中的磷酸化对脊柱生长和厌恶学习至关重要。这些研究结果表明,NMDAR的激活启动了对学习和记忆至关重要的磷酸化级联。
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引用次数: 0
Turning a negative into a positive 化消极为积极
IF 6.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-03 DOI: 10.1126/scisignal.ads7460
John F. Foley
Negatively charged lipid bilayers enhance the interaction between a chemokine and an atypical chemokine receptor.
带负电荷的脂质双分子层能增强趋化因子与非典型趋化因子受体之间的相互作用。
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引用次数: 0
Structural and functional effects of phosphopriming and scaffolding in the kinase GSK-3β 激酶 GSK-3β 中磷酸化和支架的结构和功能效应。
IF 6.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-03 DOI: 10.1126/scisignal.ado0881
Michael D. Enos, Maire Gavagan, Noel Jameson, Jesse G. Zalatan, William I. Weis
Glycogen synthase kinase 3β (GSK-3β) targets specific signaling pathways in response to distinct upstream signals. We used structural and functional studies to dissect how an upstream phosphorylation step primes the Wnt signaling component β-catenin for phosphorylation by GSK-3β and how scaffolding interactions contribute to this reaction. Our crystal structure of GSK-3β bound to a phosphoprimed β-catenin peptide confirmed the expected binding mode of the phosphoprimed residue adjacent to the catalytic site. An aspartate phosphomimic in the priming site of β-catenin adopted an indistinguishable structure but reacted approximately 1000-fold slower than the native phosphoprimed substrate. This result suggests that substrate positioning alone is not sufficient for catalysis and that native phosphopriming interactions are necessary. We also obtained a structure of GSK-3β with an extended peptide from the scaffold protein Axin that bound with greater affinity than that of previously crystallized Axin fragments. This structure neither revealed additional contacts that produce the higher affinity nor explained how substrate interactions in the GSK-3β active site are modulated by remote Axin binding. Together, our findings suggest that phosphopriming and scaffolding produce small conformational changes or allosteric effects, not captured in the crystal structures, that activate GSK-3β and facilitate β-catenin phosphorylation. These results highlight limitations in our ability to predict catalytic activity from structure and have potential implications for the role of natural phosphomimic mutations in kinase regulation and phosphosite evolution.
糖原合酶激酶 3β(GSK-3β)针对不同的上游信号靶向特定的信号通路。我们利用结构和功能研究剖析了上游磷酸化步骤如何使 Wnt 信号元件 β-catenin 在 GSK-3β 的磷酸化过程中萌发,以及支架相互作用如何促进这一反应。我们的 GSK-3β 与磷酸化β-catenin肽结合的晶体结构证实了邻近催化位点的磷酸化残基的预期结合模式。β-catenin起始位点上的天冬氨酸磷酰亚胺采用了一种难以区分的结构,但其反应速度比原生磷化底物慢约1000倍。这一结果表明,仅底物定位不足以进行催化,原生磷酸化相互作用是必要的。我们还获得了 GSK-3β 与来自支架蛋白 Axin 的延长肽的结构。这种结构既没有揭示产生更高亲和力的额外接触,也没有解释 GSK-3β 活性位点中底物的相互作用是如何受到 Axin 远端结合的调节的。总之,我们的研究结果表明,磷酸化修饰和支架作用会产生晶体结构中没有捕捉到的微小构象变化或异生效应,从而激活GSK-3β并促进β-catenin磷酸化。这些结果突显了我们从结构预测催化活性的能力的局限性,并对天然拟磷突变在激酶调控和磷酸盐进化中的作用具有潜在的影响。
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引用次数: 0
Protecting the liver with PKD1 用 PKD1 保护肝脏。
IF 6.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-27 DOI: 10.1126/scisignal.ads6258
Wei Wong
Proliferation of somatic clones deficient in PKD1 prevents fatty liver disease without resulting in tumors.
缺乏 PKD1 的体细胞克隆增殖可预防脂肪肝,但不会导致肿瘤。
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引用次数: 0
Chemokine-mediated F-actin dynamics, polarity, and migration in B lymphocytes depend on WNK1 signaling 趋化因子介导的 B 淋巴细胞 F-肌动蛋白动力学、极性和迁移依赖于 WNK1 信号传导。
IF 6.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-27 DOI: 10.1126/scisignal.ade1119
Il-Young Hwang, Ji Sung Kim, Kathleen A. Harrison, Chung Park, Chong Shan Shi, John H. Kehrl
Ligand-engaged chemokine receptors trigger nucleotide exchange in heterotrimeric Gαi proteins, which stimulates cytoskeletal reorganization and cell polarity changes. To better understand the signaling events responsible for these cellular changes, we focused on early changes in F-actin dynamics after engagement of the chemokine receptor CXCR5 in murine splenic B cells. Within 10 seconds of exposure to the CXCR5 ligand CXCL13, three-dimensional lamellar-like pseudopods and F-actin–rich ridges appeared. The transient F-actin increase depended on Gαi2/3 signaling, the PI3K/AKT pathway, ERK activation, phospholipase C activity, and Rac1/2 activation mediated by Dock2 (dedicator of cytokinesis 2). Immunoblot analyses identified the kinase WNK1 (with no lysine kinase 1) as a potential early AKT effector. Treating B cells with specific WNK inhibitors disrupted F-actin dynamics and impaired B cell polarity, motility, and chemotaxis. These changes were mimicked in a murine B cell line by CRISPR-Cas9 gene editing of Wnk1, which also suggested that WNK1 contributed to B cell proliferation. Administration of a single dose of a WNK inhibitor transiently reduced B cell motility and polarity in the lymph nodes of live mice. These results indicate that WNK1 signaling maintains B cell responsiveness to CXCL13 and suggest that pharmacological inhibition of WNK1, which is involved in cancer progression and blood pressure regulation, may affect humoral immunity.
配体参与的趋化因子受体会触发异三聚体 Gαi 蛋白的核苷酸交换,从而刺激细胞骨架重组和细胞极性变化。为了更好地了解导致这些细胞变化的信号事件,我们重点研究了小鼠脾脏B细胞与趋化因子受体CXCR5接触后F-肌动蛋白动态的早期变化。在接触 CXCR5 配体 CXCL13 的 10 秒钟内,出现了三维片状伪足和富含 F-肌动蛋白的脊。瞬时 F-肌动蛋白的增加取决于 Gαi2/3 信号传导、PI3K/AKT 通路、ERK 激活、磷脂酶 C 活性以及由 Dock2(细胞分裂驱动因子 2)介导的 Rac1/2 激活。免疫印迹分析发现,激酶 WNK1(无赖氨酸激酶 1)是一种潜在的早期 AKT 效应因子。用特异性 WNK 抑制剂处理 B 细胞会破坏 F-肌动蛋白动力学,损害 B 细胞的极性、运动性和趋化性。通过对 Wnk1 进行 CRISPR-Cas9 基因编辑,在小鼠 B 细胞系中模拟了这些变化,这也表明 WNK1 对 B 细胞增殖有贡献。服用单剂量 WNK 抑制剂可短暂降低活体小鼠淋巴结中 B 细胞的运动性和极性。这些结果表明,WNK1 信号传导可维持 B 细胞对 CXCL13 的反应性,并表明药理抑制 WNK1 可能会影响体液免疫,而 WNK1 参与癌症进展和血压调节。
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引用次数: 0
Delivery of US28 by incoming HCMV particles rapidly attenuates Akt activity to suppress HCMV lytic replication in monocytes 传入的 HCMV 颗粒输送的 US28 能迅速削弱 Akt 的活性,从而抑制 HCMV 在单核细胞中的溶解复制。
IF 6.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-27 DOI: 10.1126/scisignal.adn8727
Jamil Mahmud, Brittany W. Geiler, Juthi Biswas, Michael J. Miller, Julia E. Myers, Stephen M. Matthews, Amanda B. Wass, Christine M. O’Connor, Gary C. Chan
Establishing a nonproductive, quiescent infection within monocytes is essential for the spread of human cytomegalovirus (HCMV). We investigated the mechanisms through which HCMV establishes a quiescent infection in monocytes. US28 is a virally encoded G protein–coupled receptor (GPCR) that is essential for silent infections within cells of the myeloid lineage. We found that preformed US28 was rapidly delivered to monocytes by HCMV viral particles, whereas the de novo synthesis of US28 was delayed for several days. A recombinant mutant virus lacking US28 (US28Δ) was unable to establish a quiescent infection, resulting in a fully productive lytic infection able to produce progeny virus. Infection with US28Δ HCMV resulted in the phosphorylation of the serine and threonine kinase Akt at Ser473 and Thr308, in contrast with the phosphorylation of Akt only at Ser473 after WT viral infection. Inhibiting the dual phosphorylation of Akt prevented the lytic replication of US28Δ, and ectopic expression of a constitutively phosphorylated Akt variant triggered lytic replication of wild-type HCMV. Mechanistically, we found that US28 was necessary and sufficient to attenuate epidermal growth factor receptor (EGFR) signaling induced during the entry of WT virus, which led to the site-specific phosphorylation of Akt at Ser473. Thus, particle-delivered US28 fine-tunes Akt activity by limiting HCMV-induced EGFR activation during viral entry, enabling quiescent infection in monocytes.
在单核细胞内建立非生产性的静止感染对人类巨细胞病毒(HCMV)的传播至关重要。我们研究了 HCMV 在单核细胞内建立静止感染的机制。US28 是一种病毒编码的 G 蛋白偶联受体(GPCR),对髓系细胞内的静默感染至关重要。我们发现,HCMV 病毒颗粒能迅速将预成形的 US28 运送到单核细胞,而 US28 的重新合成则要延迟数天。缺乏 US28 的重组突变病毒(US28Δ)无法建立静止感染,导致完全生产性的溶解感染,并能产生后代病毒。感染 US28Δ HCMV 后,丝氨酸和苏氨酸激酶 Akt 在 Ser473 和 Thr308 处发生磷酸化,而感染 WT 病毒后,Akt 只在 Ser473 处发生磷酸化。抑制 Akt 的双重磷酸化可阻止 US28Δ 的溶解复制,而异位表达组成型磷酸化 Akt 变体可触发野生型 HCMV 的溶解复制。从机理上讲,我们发现 US28 对于减弱 WT 病毒进入过程中诱导的表皮生长因子受体(EGFR)信号传导是必要且充分的,这导致 Akt 在 Ser473 处发生位点特异性磷酸化。因此,颗粒递送的 US28 通过限制 HCMV 在病毒进入过程中诱导的表皮生长因子受体活化,对 Akt 活性进行了微调,从而使单核细胞中的静止感染得以实现。
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引用次数: 0
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 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 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。
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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 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。
{"title":"Hypoxia protects the gut","authors":"Annalisa M. VanHook","doi":"10.1126/scisignal.ads1861","DOIUrl":"10.1126/scisignal.ads1861","url":null,"abstract":"<div >Antibiotic-induced loss of intestinal hypoxia boosts the growth of <i>C. albicans</i> in mice.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 849","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141976967","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
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