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Cancer-associated fibroblasts produce matrix-bound vesicles that influence endothelial cell function Sci. Signal. (IF 7.3) Pub Date : 2024-03-12 Alice Santi, Emily J. Kay, Lisa J. Neilson, Lynn McGarry, Sergio Lilla, Margaret Mullin, Nikki R. Paul, Frédéric Fercoq, Grigorios Koulouras, Giovanny Rodriguez Blanco, Dimitris Athineos, Susan Mason, Mark Hughes, Gemma Thomson, Yann Kieffer, Colin Nixon, Karen Blyth, Fatima Mechta-Grigoriou, Leo M. Carlin, Sara Zanivan
Intercellular communication between different cell types in solid tumors contributes to tumor growth and metastatic dissemination. The secretome of cancer-associated fibroblasts (CAFs) plays major roles in these processes. Using human mammary CAFs, we showed that CAFs with a myofibroblast phenotype released extracellular vesicles that transferred proteins to endothelial cells (ECs) that affected their
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Cancer-associated fibroblasts produce matrix-bound vesicles that influence endothelial cell function Sci. Signal. (IF 7.3) Pub Date : 2024-03-12 Alice Santi, Emily J. Kay, Lisa J. Neilson, Lynn McGarry, Sergio Lilla, Margaret Mullin, Nikki R. Paul, Frédéric Fercoq, Grigorios Koulouras, Giovanny Rodriguez Blanco, Dimitris Athineos, Susan Mason, Mark Hughes, Gemma Thomson, Yann Kieffer, Colin Nixon, Karen Blyth, Fatima Mechta-Grigoriou, Leo M. Carlin, Sara Zanivan
Intercellular communication between different cell types in solid tumors contributes to tumor growth and metastatic dissemination. The secretome of cancer-associated fibroblasts (CAFs) plays major roles in these processes. Using human mammary CAFs, we showed that CAFs with a myofibroblast phenotype released extracellular vesicles that transferred proteins to endothelial cells (ECs) that affected their
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The activation of the adaptor protein STING depends on its interactions with the phospholipid PI4P Sci. Signal. (IF 7.3) Pub Date : 2024-03-12 Rutger D. Luteijn, Sypke R. van Terwisga, Jill E. Ver Eecke, Liberty Onia, Shivam A. Zaver, Joshua J. Woodward, Richard W. Wubbolts, David H. Raulet, Frank J. M. van Kuppeveld
Activation of the endoplasmic reticulum (ER)–resident adaptor protein STING, a component of a cytosolic DNA–sensing pathway, induces the transcription of genes encoding type I interferons (IFNs) and other proinflammatory factors. Because STING is activated at the Golgi apparatus, control of the localization and activation of STING is important in stimulating antiviral and antitumor immune responses
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eEF1A2 promotes PTEN-GSK3β-SCF complex-dependent degradation of Aurora kinase A and is inactivated in breast cancer Sci. Signal. (IF 7.3) Pub Date : 2024-03-05 Warapen Treekitkarnmongkol, Luisa M. Solis, Deivendran Sankaran, Mihai Gagea, Pankaj K. Singh, Ragini Mistry, Tristian Nguyen, Kazuharu Kai, Jiajun Liu, Kaori Sasai, Yoshimi Jitsumori, Jianwen Liu, Norio Nagao, Fabio Stossi, Michael A. Mancini, Ignacio I. Wistuba, Alastair M. Thompson, Jonathan M. Lee, Juan Cadiñanos, Kwong-Kwok Wong, Catherine M. Abbott, Aysegul A. Sahin, Suyu Liu, Hiroshi Katayama
The translation elongation factor eEF1A promotes protein synthesis. Its methylation by METTL13 increases its activity, supporting tumor growth. However, in some cancers, a high abundance of eEF1A isoforms is associated with a good prognosis. Here, we found that eEF1A2 exhibited oncogenic or tumor-suppressor functions depending on its interaction with METTL13 or the phosphatase PTEN, respectively. METTL13
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Differential protein-protein interactions underlie signaling mediated by the TCR and a 4-1BB domain–containing CAR Sci. Signal. (IF 7.3) Pub Date : 2024-03-05 Samuel A. Ritmeester-Loy, Isabella H. Draper, Eric C. Bueter, Jonathan D. Lautz, Yue Zhang-Wong, Joshua A. Gustafson, Ashley L. Wilson, Chenwei Lin, Philip R. Gafken, Michael C. Jensen, Rimas Orentas, Stephen E. P. Smith
Cells rely on activity-dependent protein-protein interactions to convey biological signals. For chimeric antigen receptor (CAR) T cells containing a 4-1BB costimulatory domain, receptor engagement is thought to stimulate the formation of protein complexes similar to those stimulated by T cell receptor (TCR)–mediated signaling, but the number and type of protein interaction–mediating binding domains
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Multiomic profiling of breast cancer cells uncovers stress MAPK-associated sensitivity to AKT degradation Sci. Signal. (IF 7.3) Pub Date : 2024-02-27 Emily C. Erickson, Inchul You, Grace Perry, Aurelien Dugourd, Katherine A. Donovan, Claire Crafter, Jeffrey W. Johannes, Stuart Williamson, Jennifer I. Moss, Susana Ros, Robert E. Ziegler, Simon T. Barry, Eric S. Fischer, Nathanael S. Gray, Ralitsa R. Madsen, Alex Toker
More than 50% of human tumors display hyperactivation of the serine/threonine kinase AKT. Despite evidence of clinical efficacy, the therapeutic window of the current generation of AKT inhibitors could be improved. Here, we report the development of a second-generation AKT degrader, INY-05-040, which outperformed catalytic AKT inhibition with respect to cellular suppression of AKT-dependent phenotypes
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ALOX5 drives the pyroptosis of CD4 + T cells and tissue inflammation in rheumatoid arthritis Sci. Signal. (IF 7.3) Pub Date : 2024-02-27 Hao Cai, Jianhua Zhang, Hua Xu, Weiwei Sun, Weijie Wu, Chen Dong, Ping Zhou, Chengbin Xue, Yunyi Nan, Yingchen Ni, Xinyuan Wu, Zhifeng Gu, Minhao Chen, Youhua Wang
Pyroptosis, an inflammatory form of programmed cell death, is linked to the pathology of rheumatoid arthritis (RA). Here, we investigated the molecular mechanism underlying pyroptosis in T cells isolated from patients with RA. Compared with healthy individuals, patients with RA had more pyroptotic CD4 + T cells in blood and synovia, which correlated with clinical measures of disease activity. Moreover
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Activation of gp130 signaling in T cells drives T H 17-mediated multi-organ autoimmunity Sci. Signal. (IF 7.3) Pub Date : 2024-02-20 Francis Baumgartner, Stefanos A. Bamopoulos, Laura Faletti, Hsiang-Jung Hsiao, Maximilian Holz, Irene Gonzalez-Menendez, Llorenç Boldo, Arik Horne, Sanket Gosavi, Ceren Özerdem, Nikita Singh, Sven Liebig, Senthilkumar Ramamoorthy, Malte Lehmann, Uta Demel, Anja A. Kühl, Tim Wartewig, Jürgen Ruland, Frank T. Wunderlich, Markus Schick, Wolfgang Walther, Stefan Rose-John, Simon Haas, Leticia Quintanilla-Martinez
The IL-6–gp130–STAT3 signaling axis is a major regulator of inflammation. Activating mutations in the gene encoding gp130 and germline gain-of-function mutations in STAT3 (STAT3 GOF ) are associated with multi-organ autoimmunity, severe morbidity, and adverse prognosis. To dissect crucial cellular subsets and disease biology involved in activated gp130 signaling, the gp130-JAK-STAT3 axis was constitutively
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Designer high-density lipoprotein particles enhance endothelial barrier function and suppress inflammation Sci. Signal. (IF 7.3) Pub Date : 2024-02-20 Yueh-Chien Lin, Steven Swendeman, Irina S. Moreira, Avishek Ghosh, Andrew Kuo, Nícia Rosário-Ferreira, Shihui Guo, Alan Culbertson, Michel V. Levesque, Andreane Cartier, Takahiro Seno, Alec Schmaier, Sylvain Galvani, Asuka Inoue, Samir M. Parikh, Garret A. FitzGerald, David Zurakowski, Maofu Liao, Robert Flaumenhaft, Zeynep H. Gümüş, Timothy Hla
High-density lipoprotein (HDL) nanoparticles promote endothelial cell (EC) function and suppress inflammation, but their utility in treating EC dysfunction has not been fully explored. Here, we describe a fusion protein named ApoA1-ApoM (A1M) consisting of apolipoprotein A1 (ApoA1), the principal structural protein of HDL that forms lipid nanoparticles, and ApoM, a chaperone for the bioactive lipid
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Mechanisms of biased agonism by Gα i/o -biased stapled peptide agonists of the relaxin-3 receptor Sci. Signal. (IF 7.3) Pub Date : 2024-02-13 Tharindunee Jayakody, Asuka Inoue, Srinivasaraghavan Kannan, Gaku Nakamura, Kouki Kawakami, Krishan Mendis, Thanh-Binh Nguyen, Jianguo Li, Deron R. Herr, Chandra S. Verma, Gavin S. Dawe
The neuropeptide relaxin-3 is composed of an A chain and a B chain held together by disulfide bonds, and it modulates functions such as anxiety and food intake by binding to and activating its cognate receptor RXFP3, mainly through the B chain. Biased ligands of RXFP3 would help to determine the molecular mechanisms underlying the activation of G proteins and β-arrestins downstream of RXFP3 that lead
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GPCR kinases differentially modulate biased signaling downstream of CXCR3 depending on their subcellular localization Sci. Signal. (IF 7.3) Pub Date : 2024-02-13 Julia Gardner, Dylan Scott Eiger, Chloe Hicks, Issac Choi, Uyen Pham, Anand Chundi, Ojas Namjoshi, Sudarshan Rajagopal
Some G protein–coupled receptors (GPCRs) demonstrate biased signaling such that ligands of the same receptor exclusively or preferentially activate certain downstream signaling pathways over others. This phenomenon may result from ligand-specific receptor phosphorylation by GPCR kinases (GRKs). GPCR signaling can also exhibit location bias because GPCRs traffic to and signal from subcellular compartments
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Cbl-b mitigates the responsiveness of naive CD8 + T cells that experience extensive tonic T cell receptor signaling Sci. Signal. (IF 7.3) Pub Date : 2024-02-06 Joel Eggert, Wendy M. Zinzow-Kramer, Yuesong Hu, Elizabeth M. Kolawole, Yuan-Li Tsai, Arthur Weiss, Brian D. Evavold, Khalid Salaita, Christopher D. Scharer, Byron B. Au-Yeung
Naive T cells experience tonic T cell receptor (TCR) signaling in response to self-antigens presented by major histocompatibility complex (MHC) in secondary lymphoid organs. We investigated how relatively weak or strong tonic TCR signals influence naive CD8 + T cell responses to stimulation with foreign antigens. The heterogeneous expression of Nur77-GFP, a transgenic reporter of tonic TCR signaling
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A mammalian-specific Alex3/Gα q protein complex regulates mitochondrial trafficking, dendritic complexity, and neuronal survival Sci. Signal. (IF 7.3) Pub Date : 2024-02-06 Ismael Izquierdo-Villalba, Serena Mirra, Yasmina Manso, Antoni Parcerisas, Javier Rubio, Jaume Del Valle, Francisco J. Gil-Bea, Fausto Ulloa, Marina Herrero-Lorenzo, Ester Verdaguer, Cristiane Benincá, Rubén D. Castro-Torres, Elena Rebollo, Gemma Marfany, Carme Auladell, Xavier Navarro, José A. Enríquez, Adolfo López de Munain, Eduardo Soriano, Anna M. Aragay
Mitochondrial dynamics and trafficking are essential to provide the energy required for neurotransmission and neural activity. We investigated how G protein–coupled receptors (GPCRs) and G proteins control mitochondrial dynamics and trafficking. The activation of Gα q inhibited mitochondrial trafficking in neurons through a mechanism that was independent of the canonical downstream PLCβ pathway. Mitoproteome
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Pannexin-3 stabilizes the transcription factor Bcl6 in a channel-independent manner to protect against vascular oxidative stress Sci. Signal. (IF 7.3) Pub Date : 2024-01-30 Abigail G. Wolpe, Melissa A. Luse, Christopher Baryiames, Wyatt J. Schug, Jacob B. Wolpe, Scott R. Johnstone, Luke S. Dunaway, Zuzanna J. Juśkiewicz, Skylar A. Loeb, Henry R. Askew Page, Yen-Lin Chen, Vikram Sabapathy, Caitlin M. Pavelec, Brent Wakefield, Eugenia Cifuentes-Pagano, Mykhaylo V. Artamonov, Avril V. Somlyo, Adam C. Straub, Rahul Sharma, Frank Beier, Eugene J. Barrett, Norbert Leitinger
Targeted degradation regulates the activity of the transcriptional repressor Bcl6 and its ability to suppress oxidative stress and inflammation. Here, we report that abundance of endothelial Bcl6 is determined by its interaction with Golgi-localized pannexin 3 (Panx3) and that Bcl6 transcriptional activity protects against vascular oxidative stress. Consistent with data from obese, hypertensive humans
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A plasma membrane–associated form of the androgen receptor enhances nuclear androgen signaling in osteoblasts and prostate cancer cells Sci. Signal. (IF 7.3) Pub Date : 2024-01-30 Hema Kalyanaraman, Darren E. Casteel, Shyamsundar Pal China, Shunhui Zhuang, Gerry R. Boss, Renate B. Pilz
Androgen binding to the androgen receptor (AR) in the cytoplasm induces the AR to translocate to the nucleus, where it regulates the expression of target genes. Here, we found that androgens rapidly activated a plasma membrane–associated signaling node that enhanced nuclear AR functions. In murine primary osteoblasts, dihydrotestosterone (DHT) binding to a membrane-associated form of AR stimulated
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TMEM216 promotes primary ciliogenesis and Hedgehog signaling through the SUFU-GLI2/GLI3 axis Sci. Signal. (IF 7.3) Pub Date : 2024-01-23 Yingying Wang, Huili Yao, Yu Zhang, Ning Mu, Tong Lu, Zhiyuan Du, Yingdi Wu, Xiaopeng Li, Min Su, Ming Shao, Xiaoyang Sun, Ling Su, Xiangguo Liu
Primary cilia are enriched in signaling receptors, and defects in their formation or function can induce conditions such as polycystic kidney disease, postaxial hexadactyly, and microphthalmia. Mammalian Hedgehog (Hh) signaling is important in the development of primary cilia, and TMEM216, a transmembrane protein that localizes to the base of cilia, is also implicated in ciliogenesis in zebrafish.
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NLRP12 interacts with NLRP3 to block the activation of the human NLRP3 inflammasome Sci. Signal. (IF 7.3) Pub Date : 2024-01-23 Jared R. Coombs, Alina Zamoshnikova, Caroline L. Holley, Madhavi P. Maddugoda, Daniel Eng Thiam Teo, Camille Chauvin, Lionel F Poulin, Nazarii Vitak, Connie M. Ross, Manasa Mellacheruvu, Rebecca C. Coll, Leonhard X. Heinz, Sabrina S. Burgener, Stefan Emming, Mathias Chamaillard, Dave Boucher, Kate Schroder
Inflammasomes are multiprotein complexes that drive inflammation and contribute to protective immunity against pathogens and immune pathology in autoinflammatory diseases. Inflammasomes assemble when an inflammasome scaffold protein senses an activating signal and forms a signaling platform with the inflammasome adaptor protein ASC. The NLRP subfamily of NOD-like receptors (NLRs) includes inflammasome
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Simultaneous substrate and ubiquitin modification recognition by bispecific antibodies enables detection of ubiquitinated RIP1 and RIP2 Sci. Signal. (IF 7.3) Pub Date : 2024-01-16 Tatiana Goncharov, László G. Kőműves, Matthias Kist, Erick R. Castellanos, Axel Witt, Anna V. Fedorova, Anita Izrael-Tomasevic, Kebing Yu, Mary Keir, Marissa L. Matsumoto, Domagoj Vucic
Ubiquitination is a posttranslational modification that is crucial for the dynamic regulation of diverse signaling pathways. To enhance our understanding of ubiquitination-mediated signaling, we generated a new class of bispecific antibodies that combine recognition of ubiquitination substrates and specific polyubiquitin linkages. RIP1-K63 and RIP1–linear (Lin) linkage polyubiquitin bispecific antibodies
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Balancing act of small GTPases downstream of plexin-A4 signaling motifs promotes dendrite elaboration in mammalian cortical neurons Sci. Signal. (IF 7.3) Pub Date : 2024-01-16 Oday Abushalbaq, Jiyeon Baek, Avraham Yaron, Tracy S. Tran
The precise development of neuronal morphologies is crucial to the establishment of synaptic circuits and, ultimately, proper brain function. Signaling by the axon guidance cue semaphorin 3A (Sema3A) and its receptor complex of neuropilin-1 and plexin-A4 has multifunctional outcomes in neuronal morphogenesis. Downstream activation of the RhoGEF FARP2 through interaction with the lysine-arginine-lysine
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The NF-κB signaling system in the immunopathogenesis of inflammatory bowel disease Sci. Signal. (IF 7.3) Pub Date : 2024-01-09 Tapas Mukherjee, Naveen Kumar, Meenakshi Chawla, Dana J. Philpott, Soumen Basak
Inflammatory bowel disease (IBD) is an idiopathic, chronic condition characterized by episodes of inflammation in the gastrointestinal tract. The nuclear factor κB (NF-κB) system describes a family of dimeric transcription factors. Canonical NF-κB signaling is stimulated by and enhances inflammation, whereas noncanonical NF-κB signaling contributes to immune organogenesis. Dysregulation of NF-κB factors
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The aldehyde dehydrogenase ALDH1B1 exerts antiviral effects through the aggregation of the adaptor MAVS Sci. Signal. (IF 7.3) Pub Date : 2024-01-09 Nina Sun, Qiaomei Cai, Yurui Zhang, Rong-Rong Zhang, Jingmei Jiang, Heng Yang, Cheng-Feng Qin, Genhong Cheng
Type I interferons (IFNs) are produced by almost all cell types and play a vital role in host defense against viral infection. Infection with an RNA virus activates receptors such as RIG-I, resulting in the recruitment of the adaptor protein MAVS to the RIG-I–like receptor (RLR) signalosome and the formation of prion-like functional aggregates of MAVS, which leads to IFN-β production. Here, we identified
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Cooperative transcriptional regulation by ATAF1 and HY5 promotes light-induced cotyledon opening in Arabidopsis thaliana Sci. Signal. (IF 7.3) Pub Date : 2024-01-02 Xiuhong Yao, Ke Fang, Kang Qiao, Jiawei Xiong, Jiayi Lan, Juan Chen, Yuang Tian, Xinke Kang, Wei Lei, Dawei Zhang, Honghui Lin
The opening of the embryonic leaves (cotyledons) as seedlings emerge from the dark soil into the light is crucial to ensure the survival of the plant. Seedlings that sprout in the dark elongate rapidly to reach light but keep their cotyledons closed. During de-etiolation, the transition from dark to light growth, elongation slows and the cotyledons open. Here, we report that the transcription factor
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Pleiotropic functions of TAO kinases and their dysregulation in neurological disorders Sci. Signal. (IF 7.3) Pub Date : 2024-01-02 Sujin Byeon, Smita Yadav
Thousand and one amino acid kinases (TAOKs) are relatively understudied and functionally pleiotropic protein kinases that have emerged as important regulators of neurodevelopment. Through their conserved amino-terminal catalytic domain, TAOKs mediate phosphorylation at serine/threonine residues in their substrates, but it is their divergent regulatory carboxyl-terminal domains that confer both exquisite
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The induction of SHP-1 degradation by TAOK3 ensures the responsiveness of T cells to TCR stimulation Sci. Signal. (IF 7.3) Pub Date : 2024-01-02 Alexandre Poirier, João Vitor Silva Ormonde, Isabelle Aubry, Belma Melda Abidin, Chu-Han Feng, Zuzet Martinez-Cordova, Ana Maria Hincapie, Chenyue Wu, Luis Alberto Pérez-Quintero, Chia-Lin Wang, Anne Claude Gingras, Joaquín Madrenas, Michel L. Tremblay
Thousand-and-one–amino acid kinase 3 (TAOK3) is a serine and threonine kinase that belongs to the STE-20 family of kinases. Its absence reduces T cell receptor (TCR) signaling and increases the interaction of the tyrosine phosphatase SHP-1, a major negative regulator of proximal TCR signaling, with the kinase LCK, a component of the core TCR signaling complex. Here, we used mouse models and human cell
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Inhibition of the lysine demethylase LSD1 modulates the balance between inflammatory and antiviral responses against coronaviruses Sci. Signal. (IF 7.3) Pub Date : 2023-12-19 Luca Mazzarella, Fabio Santoro, Roberto Ravasio, Valeria Fumagalli, Paul E. Massa, Simona Rodighiero, Elena Gavilán, Mauro Romanenghi, Bruno A. Duso, Emanuele Bonetti, Lara Manganaro, Rani Pallavi, Deborah Trastulli, Isabella Pallavicini, Claudia Gentile, Silvia Monzani, Tommaso Leonardi, Sebastiano Pasqualato, Gabriele Buttinelli, Angela Di Martino, Giorgio Fedele, Ilaria Schiavoni, Paola Stefanelli
Innate immune responses to coronavirus infections are highly cell specific. Tissue-resident macrophages, which are infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients but are inconsistently infected in vitro, exert critical but conflicting effects by secreting both antiviral type I interferons (IFNs) and tissue-damaging inflammatory cytokines. Steroids, the only class
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A noncanonical IRAK4-IRAK1 pathway counters DNA damage–induced apoptosis independently of TLR/IL-1R signaling Sci. Signal. (IF 7.3) Pub Date : 2023-12-19 Yuanyuan Li, Richa B. Shah, Samanta Sarti, Alicia L. Belcher, Brian J. Lee, Andrej Gorbatenko, Francesca Nemati, Honglin Yu, Zoe Stanley, Mahbuba Rahman, Zhengping Shao, Jose M. Silva, Shan Zha, Samuel Sidi
Interleukin-1 receptor (IL-1R)–associated kinases (IRAKs) are core effectors of Toll-like receptors (TLRs) and IL-1R in innate immunity. Here, we found that IRAK4 and IRAK1 together inhibited DNA damage–induced cell death independently of TLR or IL-1R signaling. In human cancer cells, IRAK4 was activated downstream of ATR kinase in response to double-strand breaks (DSBs) induced by ionizing radiation
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RHOA L57V drives the development of diffuse gastric cancer through IGF1R-PAK1-YAP1 signaling Sci. Signal. (IF 7.3) Pub Date : 2023-12-19 Antje Schaefer, Richard G. Hodge, Haisheng Zhang, G. Aaron Hobbs, Julien Dilly, Minh V. Huynh, Craig M. Goodwin, Feifei Zhang, J. Nathaniel Diehl, Mariaelena Pierobon, Elisa Baldelli, Sehrish Javaid, Karson Guthrie, Naim U. Rashid, Emanuel F. Petricoin, Adrienne D. Cox, William C. Hahn, Andrew J. Aguirre, Adam J. Bass, Channing J. Der
Cancer-associated mutations in the guanosine triphosphatase (GTPase) RHOA are found at different locations from the mutational hotspots in the structurally and biochemically related RAS. Tyr 42 -to-Cys (Y42C) and Leu 57 -to-Val (L57V) substitutions are the two most prevalent RHOA mutations in diffuse gastric cancer (DGC). RHOA Y42C exhibits a gain-of-function phenotype and is an oncogenic driver in
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RHOA drivers take alternate routes in gastric cancer Sci. Signal. (IF 7.3) Pub Date : 2023-12-19 Dorothy Benton, Jonathan Chernoff
Oncogenic small guanosine triphosphatases (GTPases) are often characterized by a limited set of activating mutations that affect their intrinsic biochemical function, but RHOA—which is frequently mutated in gastric cancer—appears not to have read the instruction manual. Having previously characterized the Y42C RHOA mutation in gastric cancer, in this issue of Science Signaling , Schaefer et al. take
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Nonself RNA rewires IFN-β signaling: A mathematical model of the innate immune response Sci. Signal. (IF 7.3) Pub Date : 2023-12-12 Zbigniew Korwek, Maciej Czerkies, Joanna Jaruszewicz-Błońska, Wiktor Prus, Ilona Kosiuk, Marek Kochańczyk, Tomasz Lipniacki
Type I interferons (IFNs) are key coordinators of the innate immune response to viral infection, which, through activation of the transcriptional regulators STAT1 and STAT2 (STAT1/2) in bystander cells, induce the expression of IFN-stimulated genes (ISGs). Here, we showed that in cells transfected with poly(I:C), an analog of viral RNA, the transcriptional activity of STAT1/2 was terminated because
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Proximity proteomic analysis of the NRF family reveals the Parkinson’s disease protein ZNF746/PARIS as a co-complexed repressor of NRF2 Sci. Signal. (IF 7.3) Pub Date : 2023-12-12 Kyle M. LaPak, Soma Saeidi, Ilah Bok, Nathan T. Wamsley, Isaac B. Plutzer, Dhaval P. Bhatt, Jingqin Luo, Ghazaleh Ashrafi, M. Ben Major
The nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor activates cytoprotective and metabolic gene expression in response to various electrophilic stressors. Constitutive NRF2 activity promotes cancer progression, whereas decreased NRF2 function contributes to neurodegenerative diseases. We used proximity proteomic analysis to define protein networks for NRF2 and its family members
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Palmitoylated Sept8-204 modulates learning and anxiety by regulating filopodia arborization and actin dynamics Sci. Signal. (IF 7.3) Pub Date : 2023-12-05 Huicong Liu, Peipei Yan, Can Wu, Muding Rao, Jiangli Zhu, Luxian Lv, Wenqiang Li, Yinming Liang, Shiqian Qi, Kefeng Lu, Eryan Kong
Septin proteins are involved in diverse physiological functions, including the formation of specialized cytoskeletal structures. Septin 8 (Sept8) is implicated in spine morphogenesis and dendritic branching through palmitoylation. We explored the role and regulation of a Sept8 variant in human neural-like cells and in the mouse brain. We identified Sept8-204 as a brain-specific variant of Sept8 that
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STAT3 palmitoylation initiates a positive feedback loop that promotes the malignancy of hepatocellular carcinoma cells in mice Sci. Signal. (IF 7.3) Pub Date : 2023-12-05 Yi Jiang, Yuejie Xu, Chengliang Zhu, Guifang Xu, Lei Xu, Zijian Rao, Lixing Zhou, Ping Jiang, Sara Malik, Jingyuan Fang, Hening Lin, Mingming Zhang
Constitutive activation of the transcription factor STAT3 (signal transducer and activator of transcription 3) contributes to the malignancy of many cancers such as hepatocellular carcinoma (HCC) and is associated with poor prognosis. STAT3 activity is increased by the reversible palmitoylation of Cys 108 by the palmitoyltransferase DHHC7 (encoded by ZDHHC7 ). Here, we investigated the consequences
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PI3K-C2β limits mTORC1 signaling and angiogenic growth Sci. Signal. (IF 7.3) Pub Date : 2023-11-28 Piotr Kobialka, Judith Llena, Nerea Deleyto-Seldas, Margalida Munar-Gelabert, Jose A. Dengra, Pilar Villacampa, Alba Albinyà-Pedrós, Laia Muixi, Jorge Andrade, Hielke van Splunder, Ana Angulo-Urarte, Michael Potente, Joaquim Grego-Bessa, Sandra D. Castillo, Bart Vanhaesebroeck, Alejo Efeyan, Mariona Graupera
Phosphoinositide 3-kinases (PI3Ks) phosphorylate intracellular inositol lipids to regulate signaling and intracellular vesicular trafficking. Mammals have eight PI3K isoforms, of which class I PI3Kα and class II PI3K-C2α are essential for vascular development. The class II PI3K-C2β is also abundant in endothelial cells. Using in vivo and in vitro approaches, we found that PI3K-C2β was a critical regulator
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PD-1 inhibits T cell actin remodeling at the immunological synapse independently of its signaling motifs Sci. Signal. (IF 7.3) Pub Date : 2023-11-28 Noémie Paillon, Violette Mouro, Stéphanie Dogniaux, Mathieu Maurin, Juan-José Saez Pons, Hermine Ferran, Laurence Bataille, Andrés Ernesto Zucchetti, Claire Hivroz
Engagement of the receptor programmed cell death molecule 1 (PD-1) by its ligands PD-L1 and PD-L2 inhibits T cell–mediated immune responses. Blocking such signaling provides the clinical effects of PD-1–targeted immunotherapy. Here, we investigated the mechanisms underlying PD-1–mediated inhibition. Because dynamic actin remodeling is crucial for T cell functions, we characterized the effects of PD-1
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Actin’ off: PD-1 suppresses F-actin rearrangement and degranulation at the immunological synapse Sci. Signal. (IF 7.3) Pub Date : 2023-11-28 Sayanti Acharya, Sudha Kumari
Programmed cell death molecule 1 (PD-1) is a negative regulator of T cell activation; however, the mechanisms by which it acts are unclear. In this issue of Science Signaling , Paillon et al . show that PD-1 inhibits actin cytoskeletal rearrangements and associated effector responses in cytotoxic T cells.
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Beige is the color of keeping weight off. Sci. Signal. (IF 7.3) Pub Date : 2023-11-21 Wei Wong
A monocyte population induced by weight loss promotes white fat beiging to limit weight regain.
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Plant MDL proteins synergize with the cytokine MIF at CXCR2 and CXCR4 receptors in human cells Sci. Signal. (IF 7.3) Pub Date : 2023-11-21 Lukas Spiller, Ramu Manjula, Franz Leissing, Jerome Basquin, Priscila Bourilhon, Dzmitry Sinitski, Markus Brandhofer, Sophie Levecque, Simona Gerra, Björn Sabelleck, Lin Zhang, Regina Feederle, Andrew Flatley, Adrian Hoffmann, Ralph Panstruga, Jürgen Bernhagen, Elias Lolis
Mammalian macrophage migration inhibitory factor (MIF) and its paralog, D-dopachrome tautomerase, are multifunctional inflammatory cytokines. Plants have orthologous MIF and D-dopachrome tautomerase–like (MDL) proteins that mimic some of the effects of MIF on immune cells in vitro. We explored the structural and functional similarities between the three Arabidopsis thaliana MDLs and MIF. X-ray crystallography
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Enteric glia promote visceral hypersensitivity during inflammation through intercellular signaling with gut nociceptors Sci. Signal. (IF 7.3) Pub Date : 2023-11-21 Wilmarie Morales-Soto, Jacques Gonzales, William F. Jackson, Brian D. Gulbransen
Inflammation in the intestines causes abdominal pain that is challenging to manage. The terminals of sensory neurons innervating the gut are surrounded by glia. Here, using a mouse model of acute colitis, we found that enteric glia contribute to visceral pain by secreting factors that sensitized sensory nerves innervating the gut in response to inflammation. Acute colitis induced a transient increase
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Vasodilators activate the anion channel TMEM16A in endothelial cells to reduce blood pressure Sci. Signal. (IF 7.3) Pub Date : 2023-11-14 Alejandro Mata-Daboin, Tessa A. C. Garrud, Carlos Fernandez-Pena, Dieniffer Peixoto-Neves, M. Dennis Leo, Angelica K. Bernardelli, Purnima Singh, Kafait U. Malik, Jonathan H. Jaggar
Systemic blood pressure is acutely controlled by total peripheral resistance as determined by the diameter of small arteries and arterioles, the contractility of which is regulated by endothelial cells lining the lumen of blood vessels. We investigated the physiological functions of the chloride (Cl − ) channel TMEM16A in endothelial cells. TMEM16A channels generated calcium (Ca 2+ )–activated Cl −
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Impaired intracellular Ca 2+ signaling contributes to age-related cerebral small vessel disease in Col4a1 mutant mice Sci. Signal. (IF 7.3) Pub Date : 2023-11-14 Evan Yamasaki, Pratish Thakore, Sher Ali, Alfredo Sanchez Solano, Xiaowei Wang, Xiao Gao, Cassandre Labelle-Dumais, Myriam M. Chaumeil, Douglas B. Gould, Scott Earley
Humans and mice with mutations in COL4A1 and COL4A2 manifest hallmarks of cerebral small vessel disease (cSVD). Mice with a missense mutation in Col4a1 at amino acid 1344 ( Col4a1 +/G1344D ) exhibit age-dependent intracerebral hemorrhages (ICHs) and brain lesions. Here, we report that this pathology was associated with the loss of myogenic vasoconstriction, an intrinsic vascular response essential
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The TMEM16A anion channel as a versatile regulator of vascular tone Sci. Signal. (IF 7.3) Pub Date : 2023-11-14 Paolo Tammaro
The TMEM16A channel represents a key depolarizing mechanism in arterial smooth muscle and contractile pericytes, where it is activated by several endogenous contractile agonists. In this issue of Science Signaling , Mata-Daboin et al. demonstrate a previously unidentified role for TMEM16A in endothelial cells for acetylcholine-mediated vasorelaxation. Collectively, TMEM16A serves as a transducer of
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A conserved mechanism for JNK-mediated loss of Notch function in advanced prostate cancer Sci. Signal. (IF 7.3) Pub Date : 2023-11-07 Cheng-Wei Wang, Marie Clémot, Takao Hashimoto, Johnny A. Diaz, Lauren M. Goins, Andrew S. Goldstein, Raghavendra Nagaraj, Utpal Banerjee
Dysregulated Notch signaling is a common feature of cancer; however, its effects on tumor initiation and progression are highly variable, with Notch having either oncogenic or tumor-suppressive functions in various cancers. To better understand the mechanisms that regulate Notch function in cancer, we studied Notch signaling in a Drosophila tumor model, prostate cancer–derived cell lines, and tissue
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Chemokines form complex signals during inflammation and disease that can be decoded by extracellular matrix proteoglycans Sci. Signal. (IF 7.3) Pub Date : 2023-11-07 Amanda J. L. Ridley, Yaqing Ou, Richard Karlsson, Nabina Pun, Holly L. Birchenough, Iashia Z. Mulholland, Mary L. Birch, Andrew S. MacDonald, Thomas A. Jowitt, Craig Lawless, Rebecca L. Miller, Douglas P. Dyer
Chemokine-driven leukocyte recruitment is a key component of the immune response and of various diseases. Therapeutically targeting the chemokine system in inflammatory disease has been unsuccessful, which has been attributed to redundancy. We investigated why chemokines instead have specific, specialized functions, as demonstrated by multiple studies. We analyzed the expression of genes encoding chemokines
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Sleep and longevity tied to glia. Sci. Signal. (IF 7.3) Pub Date : 2023-10-31 Leslie K Ferrarelli
Glia mediate two-way signaling between the brain and gut that supports sleep and healthy aging.
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Integrin-dependent recruitment of Src to ROS-producing endosomes in osteoarthritic cartilage Sci. Signal. (IF 7.3) Pub Date : 2023-10-31 Mary B. Goldring
Fibronectin (FN) fragments stimulate catabolic signaling, and, by binding to integrins, they induce chondrocytes to increase the production of matrix metalloproteinases, including MMP-13. In this issue of Science Signaling , Miao et al. reveal that internalization of a FN fragment, but not intact FN, by α5β1 integrin results in the formation of ROS-producing endosomes (redoxosomes) through which chondrocytes
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DOK3 promotes atopic dermatitis by enabling the phosphatase PP4C to inhibit the T cell signaling mediator CARD11 Sci. Signal. (IF 7.3) Pub Date : 2023-10-31 Jia Tong Loh, Joey Kay Hui Teo, Srinivasaraghavan Kannan, Chandra S. Verma, Anand Kumar Andiappan, Hong-Hwa Lim, Kong-Peng Lam
The scaffolding protein CARD11 is a critical mediator of antigen receptor signaling in lymphocytes. Hypomorphic (partial loss-of-function) mutations in CARD11 are associated with the development of severe atopic dermatitis, in which T cell receptor signaling is reduced and helper T cell differentiation is skewed to an allergy-associated type 2 phenotype. Here, we found that the docking protein DOK3
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Redox-active endosomes mediate α5β1 integrin signaling and promote chondrocyte matrix metalloproteinase production in osteoarthritis Sci. Signal. (IF 7.3) Pub Date : 2023-10-31 Michael Z. Miao, Qian Peter Su, Yang Cui, Edward M. Bahnson, Gang Li, Menglin Wang, Yuchen Yang, John A. Collins, Di Wu, Qisheng Gu, Susan Chubinskaya, Brian O. Diekman, Kenneth M. Yamada, Richard F. Loeser
Mechanical cues sensed by integrins induce cells to produce proteases to remodel the extracellular matrix. Excessive protease production occurs in many degenerative diseases, including osteoarthritis, in which articular cartilage degradation is associated with the genesis of matrix protein fragments that can activate integrins. We investigated the mechanisms by which integrin signals may promote protease
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Human IL-17A protein production is controlled through a PIP5K1α-dependent translational checkpoint Sci. Signal. (IF 7.3) Pub Date : 2023-10-24 Shankar K. Revu, Wenjuan Yang, Dhivyaa Rajasundaram, Alexander Brady, Saikat Majumder, Sarah L. Gaffen, William Hawse, Zongqi Xia, Mandy J. McGeachy
The cytokine interleukin-17 (IL-17) is secreted by T helper 17 (T H 17) cells and is beneficial for microbial control; however, it also causes inflammation and pathological tissue remodeling in autoimmunity. Hence, T H 17 cell differentiation and IL-17 production must be tightly regulated, but, to date, this has been defined only in terms of transcriptional control. Phosphatidylinositols are second
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Binding of CaMKII to the NMDA receptor is sufficient for long-term potentiation Sci. Signal. (IF 7.3) Pub Date : 2023-10-24 Johannes W. Hell
Learning and the underlying long-lasting increases in glutamatergic synapse strength [called long-term potentiation (LTP)] require both Ca 2+ influx through NMDA-type glutamate receptors (NMDARs) and the kinase CaMKII. New evidence now suggests that CaMKII can induce LTP purely by binding to the NMDAR subunit GluN2B and does not require the catalytic activity of the kinase.
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Purinergic P2Y2 receptor–induced activation of endothelial TRPV4 channels mediates lung ischemia-reperfusion injury Sci. Signal. (IF 7.3) Pub Date : 2023-10-24 Maniselvan Kuppusamy, Huy Q. Ta, Hannah N. Davenport, Abhishek Bazaz, Astha Kulshrestha, Zdravka Daneva, Yen-Lin Chen, Philip W. Carrott, Victor E. Laubach, Swapnil K. Sonkusare
Lung ischemia-reperfusion injury (IRI), characterized by inflammation, vascular permeability, and lung edema, is the major cause of primary graft dysfunction after lung transplantation. Here, we investigated the cellular mechanisms underlying lung IR–induced activation of endothelial TRPV4 channels, which play a central role in lung edema and dysfunction after IR. In a left lung hilar-ligation model
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Multivalent, asymmetric IL-2–Fc fusions show enhanced selectivity for regulatory T cells Sci. Signal. (IF 7.3) Pub Date : 2023-10-17 Brian T. Orcutt-Jahns, Peter C. Emmel, Eli M. Snyder, Scott D. Taylor, Aaron S. Meyer
The cytokine interleukin-2 (IL-2) has the potential to treat autoimmune disease but is limited by its modest specificity toward immunosuppressive regulatory T (T reg ) cells. IL-2 receptors consist of combinations of α, β, and γ chains of variable affinity and cell specificity. Engineering IL-2 to treat autoimmunity has primarily focused on retaining binding to the relatively T reg -selective, high-affinity
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Phosphatidic acid binding to Patched contributes to the inhibition of Smoothened and Hedgehog signaling in Drosophila wing development Sci. Signal. (IF 7.3) Pub Date : 2023-10-17 Jie Zhang, Yajuan Liu, Chi Wang, Craig W. Vander Kooi, Jianhang Jia
Hedgehog (Hh) signaling controls growth and patterning during embryonic development and homeostasis in adult tissues. Hh binding to the receptor Patched (Ptc) elicits intracellular signaling by relieving Ptc-mediated inhibition of the transmembrane protein Smoothened (Smo). We uncovered a role for the lipid phosphatidic acid (PA) in the regulation of the Hh pathway in Drosophila melanogaster . Deleting
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Membrane-proximal motifs encode differences in signaling strength between type I and III interferon receptors Sci. Signal. (IF 7.3) Pub Date : 2023-10-10 Emily V. Mesev, Aaron E. Lin, Emma G. Guare, Brigitte L. Heller, Florian Douam, Britt Adamson, Jared E. Toettcher, Alexander Ploss
Interferons (IFNs) play crucial roles in antiviral defenses. Despite using the same Janus-activated kinase (JAK)–signal transducer and activator of transcription (STAT) signaling cascade, type I and III IFN receptors differ in the magnitude and dynamics of their signaling in terms of STAT phosphorylation, gene transcription, and antiviral responses. These differences are not due to ligand-binding affinity
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TRIM55 promotes noncanonical NF-κB signaling and B cell–mediated immune responses by coordinating p100 ubiquitination and processing Sci. Signal. (IF 7.3) Pub Date : 2023-10-10 Liangbin Lin, Hui Yu, Li Li, Wenyong Yang, Xueying Chen, Yanqiu Gong, Qingqiang Lei, Zhonghan Li, Zhaocai Zhou, Lunzhi Dai, Huiyuan Zhang, Hongbo Hu
The ubiquitination-dependent processing of NF-κB2 (also known as p100) is a critical step in the activation of the noncanonical NF-κB pathway. We investigated the molecular mechanisms regulating this process and showed that TRIM55 was the E3 ubiquitin ligase that mediated the ubiquitination of p100 and coordinated its processing. TRIM55 deficiency impaired noncanonical NF-κB activation and B cell function
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The ligand-dependent suppression of TCR signaling by the immune checkpoint receptor LAG3 depends on the cytoplasmic RRFSALE motif Sci. Signal. (IF 7.3) Pub Date : 2023-10-03 Katharina Aigner-Radakovics, Annika De Sousa Linhares, Benjamin Salzer, Manfred Lehner, Shiva Izadi, Alexandra Castilho, Winfried F. Pickl, Judith Leitner, Peter Steinberger
Lymphocyte activation gene 3 (LAG3) is an inhibitory immune checkpoint receptor that restrains autoimmune and antitumor responses, but its evolutionarily conserved cytoplasmic tail lacks classical inhibitory motifs. Major histocompatibility complex class II (MHC class II) is an established LAG3 ligand, and fibrinogen-like protein 1 (FGL1), lymph node sinusoidal endothelial cell C-type lectin (LSECtin)
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Signaling dynamics distinguish high- and low-priority neutrophil chemoattractant receptors Sci. Signal. (IF 7.3) Pub Date : 2023-10-03 Stefan M. Lundgren, Briana L. Rocha-Gregg, Emel Akdoğan, Maya N. Mysore, Samantha Hayes, Sean R. Collins
Human neutrophils respond to multiple chemoattractants to guide their migration from the vasculature to sites of infection and injury, where they clear pathogens and amplify inflammation. To properly focus their responses during this complex navigation, neutrophils prioritize pathogen- and injury-derived signals over long-range inflammatory signals, such as the leukotriene LTB4, secreted by host cells
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Stressed Hippo kinase turns to autophagy. Sci. Signal. (IF 7.3) Pub Date : 2023-09-26 Leslie K Ferrarelli
The Hippo kinase MAP4K2 takes a YAP-independent path to tolerating energy stress.
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Transcriptomics-inferred dynamics of SARS-CoV-2 interactions with host epithelial cells Sci. Signal. (IF 7.3) Pub Date : 2023-09-26 Lukas Adam, Megan Stanifer, Fabian Springer, Jan Mathony, Maik Brune, Chiara Di Ponzio, Roland Eils, Steeve Boulant, Dominik Niopek, Stefan M. Kallenberger
Virus-host interactions can reveal potentially effective and selective therapeutic targets for treating infection. Here, we performed an integrated analysis of the dynamics of virus replication and the host cell transcriptional response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using human Caco-2 colon cancer cells as a model. Time-resolved RNA sequencing revealed that
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B cell responses to membrane-presented antigens require the function of the mechanosensitive cation channel Piezo1 Sci. Signal. (IF 7.3) Pub Date : 2023-09-26 Kihyuck Kwak, Haewon Sohn, Rachel George, Charles Torgbor, Javier Manzella-Lapeira, Joseph Brzostowski, Susan K. Pierce
The demand for a vaccine for coronavirus disease 2019 (COVID-19) highlighted gaps in our understanding of the requirements for B cell responses to antigens, particularly to membrane-presented antigens, as occurs in vivo. We found that human B cell responses to membrane-presented antigens required the function of Piezo1, a plasma membrane mechanosensitive cation channel. Simply making contact with a
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Opposing roles of RUBCN isoforms in autophagy and memory B cell generation Sci. Signal. (IF 7.3) Pub Date : 2023-09-19 Chao-Yuan Tsai, Shuhei Sakakibara, Yu-Diao Kuan, Hiroko Omori, Maruwa Ali El Hussien, Daisuke Okuzaki, Shiou-Ling Lu, Takeshi Noda, Keisuke Tabata, Shuhei Nakamura, Tamotsu Yoshimori, Hitoshi Kikutani
RUBCN (also known as Rubicon) was originally identified as a negative regulator of autophagy, a process by which cells degrade and recycle damaged components or organelles and that requires the activity of the class III PI3K VPS34 and the mTORC1 protein complex. Here, we characterized the role of a shorter isoform, RUBCN 100 , as an autophagy-promoting factor in B cells. RUBCN 100 was translated from