Science Signaling最新文献_第4页

Aging and age-related disorders, cell by cell 逐个细胞看衰老和老年相关疾病

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-09-10 DOI: 10.1126/scisignal.ads9401

Leslie K. Ferrarelli

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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

Science Signaling Pub Date : 2024-09-10 DOI: 10.1126/scisignal.adf9388

Liming Liao, Ping Yang, Weilong Zhang, Shuyu Yu, Hongmei Jing, Xiaofeng Zheng

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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

Science Signaling 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

{"title":"Signal flow in the NMDA receptor–dependent phosphoproteome regulates postsynaptic plasticity for aversive learning","authors":"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","doi":"10.1126/scisignal.ado9852","DOIUrl":"10.1126/scisignal.ado9852","url":null,"abstract":"<div >Structural plasticity of dendritic spines in the nucleus accumbens (NAc) is crucial for learning from aversive experiences. Activation of NMDA receptors (NMDARs) stimulates Ca<sup>2+</sup>-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 Ca<sup>2+</sup>-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.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 853","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.ado9852","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142165826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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

Science Signaling Pub Date : 2024-09-03 DOI: 10.1126/scisignal.ads7460

John F. Foley

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

Science Signaling Pub Date : 2024-09-03 DOI: 10.1126/scisignal.ado0881

Michael D. Enos, Maire Gavagan, Noel Jameson, Jesse G. Zalatan, William I. Weis

{"title":"Structural and functional effects of phosphopriming and scaffolding in the kinase GSK-3β","authors":"Michael D. Enos, Maire Gavagan, Noel Jameson, Jesse G. Zalatan, William I. Weis","doi":"10.1126/scisignal.ado0881","DOIUrl":"10.1126/scisignal.ado0881","url":null,"abstract":"<div >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.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 852","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142127159","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}

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Protecting the liver with PKD1 用 PKD1 保护肝脏。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-08-27 DOI: 10.1126/scisignal.ads6258

Wei Wong

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

Science Signaling 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

{"title":"Chemokine-mediated F-actin dynamics, polarity, and migration in B lymphocytes depend on WNK1 signaling","authors":"Il-Young Hwang, Ji Sung Kim, Kathleen A. Harrison, Chung Park, Chong Shan Shi, John H. Kehrl","doi":"10.1126/scisignal.ade1119","DOIUrl":"10.1126/scisignal.ade1119","url":null,"abstract":"<div >Ligand-engaged chemokine receptors trigger nucleotide exchange in heterotrimeric Gα<sub>i</sub> 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 Gα<sub>i2/3</sub> 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<i> Wnk1</i>, 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.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 851","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142082418","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}

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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

Science Signaling 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

{"title":"Delivery of US28 by incoming HCMV particles rapidly attenuates Akt activity to suppress HCMV lytic replication in monocytes","authors":"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","doi":"10.1126/scisignal.adn8727","DOIUrl":"10.1126/scisignal.adn8727","url":null,"abstract":"<div >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 Ser<sup>473</sup> and Thr<sup>308</sup>, in contrast with the phosphorylation of Akt only at Ser<sup>473</sup> 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 Ser<sup>473</sup>. Thus, particle-delivered US28 fine-tunes Akt activity by limiting HCMV-induced EGFR activation during viral entry, enabling quiescent infection in monocytes.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 851","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142082419","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

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

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

{"title":"The host protease KLK5 primes and activates spike proteins to promote human betacoronavirus replication and lung inflammation","authors":"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","doi":"10.1126/scisignal.adn3785","DOIUrl":"10.1126/scisignal.adn3785","url":null,"abstract":"<div >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.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 850","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142009813","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}

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Stroke of DNA DNA 笔触

IF 6.7 1区生物学

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

Amy E. Baek

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