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Science Signaling

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https://www.readbyqxmd.com/read/29991651/ikk-promotes-cytokine-induced-and-cancer-associated-ampk-activity-and-attenuates-phenformin-induced-cell-death-in-lkb1-deficient-cells
#1
Ricardo J Antonia, Albert S Baldwin
The 5' AMP-activated protein kinase (AMPK) is an energy sensor that is activated upon phosphorylation of Thr172 in its activation loop by the kinase LKB1, CAMKK2, or TAK1. TAK1-dependent AMPK phosphorylation of Thr172 is less well characterized than phosphorylation of this site by LKB1 or CAMKK2. An important target of TAK1 is IκB kinase (IKK), which controls the activation of the transcription factor NF-κB. We tested the hypothesis that IKK acted downstream of TAK1 to activate AMPK by phosphorylating Thr172 IKK was required for the phosphorylation of Thr172 in AMPK in response to treatment with the inflammatory cytokine IL-1β or TNF-α or upon TAK1 overexpression...
July 10, 2018: Science Signaling
https://www.readbyqxmd.com/read/29991650/the-costimulatory-molecule-cd226-signals-through-vav1-to-amplify-tcr-signals-and-promote-il-17-production-by-cd4-t-cells
#2
Guillaume Gaud, Romain Roncagalli, Karima Chaoui, Isabelle Bernard, Julien Familiades, Céline Colacios, Sahar Kassem, Bernard Monsarrat, Odile Burlet-Schiltz, Anne Gonzalez de Peredo, Bernard Malissen, Abdelhadi Saoudi
The activation of T cells requires the guanine nucleotide exchange factor VAV1. Using mice in which a tag for affinity purification was attached to endogenous VAV1 molecules, we analyzed by quantitative mass spectrometry the signaling complex that assembles around activated VAV1. Fifty VAV1-binding partners were identified, most of which had not been previously reported to participate in VAV1 signaling. Among these was CD226, a costimulatory molecule of immune cells. Engagement of CD226 induced the tyrosine phosphorylation of VAV1 and synergized with T cell receptor (TCR) signals to specifically enhance the production of interleukin-17 (IL-17) by primary human CD4+ T cells...
July 10, 2018: Science Signaling
https://www.readbyqxmd.com/read/29991649/mitochondrial-redox-sensing-by-the-kinase-atm-maintains-cellular-antioxidant-capacity
#3
Yichong Zhang, Ji-Hoon Lee, Tanya T Paull, Sarah Gehrke, Angelo D'Alessandro, Qianhui Dou, Vadim N Gladyshev, Elizabeth A Schroeder, Samantha K Steyl, Brooke E Christian, Gerald S Shadel
Mitochondria are integral to cellular energy metabolism and ATP production and are involved in regulating many cellular processes. Mitochondria produce reactive oxygen species (ROS), which not only can damage cellular components but also participate in signal transduction. The kinase ATM, which is mutated in the neurodegenerative, autosomal recessive disease ataxia-telangiectasia (A-T), is a key player in the nuclear DNA damage response. However, ATM also performs a redox-sensing function mediated through formation of ROS-dependent disulfide-linked dimers...
July 10, 2018: Science Signaling
https://www.readbyqxmd.com/read/29970604/nuclear-import-pathway-key-to-rescuing-dominant-progerin-phenotypes
#4
REVIEW
Katherine L Wilson
In this issue of Science Signaling , Larrieu et al show that an acetyltransferase inhibitor that rescues many dominant nuclear phenotypes caused by progerin, a truncated form of lamin A, does so by releasing the specialized nuclear import receptor TNPO1 from sequestration by microtubules. This release enables TNPO1-dependent import of specific cargoes, including the nuclear pore protein Nup153 and the heterogeneous nuclear ribonucleoprotein hnRNPA1, thus restoring the functionality of nuclear pore complexes, rebalancing the nucleocytoplasmic Ran gradient, and normalizing gene expression...
July 3, 2018: Science Signaling
https://www.readbyqxmd.com/read/29970603/inhibition-of-the-acetyltransferase-nat10-normalizes-progeric-and-aging-cells-by-rebalancing-the-transportin-1-nuclear-import-pathway
#5
Delphine Larrieu, Emmanuelle Viré, Samuel Robson, Sophia Y Breusegem, Tony Kouzarides, Stephen P Jackson
Hutchinson-Gilford progeria syndrome (HGPS) is an incurable premature aging disease. Identifying deregulated biological processes in HGPS might thus help define novel therapeutic strategies. Fibroblasts from HGPS patients display defects in nucleocytoplasmic shuttling of the GTP-bound form of the small GTPase Ran (RanGTP), which leads to abnormal transport of proteins into the nucleus. We report that microtubule stabilization in HGPS cells sequestered the nonclassical nuclear import protein Transportin-1 (TNPO1) in the cytoplasm, thus affecting the nuclear localization of its cargo, including the nuclear pore protein NUP153...
July 3, 2018: Science Signaling
https://www.readbyqxmd.com/read/29970602/tomosyn-functions-as-a-pkc%C3%AE-regulated-fusion-clamp-in-mast-cell-degranulation
#6
Iris K Madera-Salcedo, Luca Danelli, Neeraj Tiwari, Bárbara Dema, Emeline Pacreau, Shamila Vibhushan, Joëlle Birnbaum, Chantal Agabriel, Valérie Liabeuf, Caroline Klingebiel, Gaël Menasche, Marina Macias-Silva, Marc Benhamou, Nicolas Charles, Claudia González-Espinosa, Joana Vitte, Ulrich Blank
Soluble N -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) family proteins mediate membrane fusion critical for vesicular transport and cellular secretion. Mast cells rely on SNARE-mediated membrane fusion for degranulation stimulated by crosslinking of immunoglobulin E (IgE) bound to the Fcε receptor (FcεRI). We investigated the mechanisms downstream of receptor activation that control degranulation. We found that the SNARE binding protein tomosyn-1 (also known as STXBP5) inhibited FcεRI-stimulated degranulation of mast cells...
July 3, 2018: Science Signaling
https://www.readbyqxmd.com/read/29970601/proteomic-analysis-of-s-nitrosylated-nuclear-proteins-in-rat-cortical-neurons
#7
Jacob G Smith, Sarah G Aldous, Catia Andreassi, Giovanni Cuda, Marco Gaspari, Antonella Riccio
Neurons modulate gene expression in response to extrinsic signals to enable brain development, cognition, and learning and to process stimuli that regulate systemic physiological functions. This signal-to-gene communication is facilitated by posttranslational modifications such as S-nitrosylation, the covalent attachment of a nitric oxide (NO) moiety to cysteine thiols. In the cerebral cortex, S-nitrosylation of histone deacetylase 2 (HDAC2) is required for gene transcription during neuronal development, but few other nuclear targets of S-nitrosylation have been identified to date...
July 3, 2018: Science Signaling
https://www.readbyqxmd.com/read/29970600/evolution-of-human-chicken-alligator-frog-and-zebrafish-mineralocorticoid-receptors-allosteric-influence-on-steroid-specificity
#8
Yoshinao Katsu, Kaori Oka, Michael E Baker
Although multiple steroid ligands of the glucocorticoid, mineralocorticoid, and progestin families bind to and regulate the activity of mineralocorticoid receptors (MRs), the responses to these ligands differ across species. To understand how the different domains of MRs contribute to the ligand-induced activation or inhibition of MR activity, we studied the response to eight steroids (aldosterone, 11-deoxycorticosterone, 11-deoxycortisol, cortisol, corticosterone, progesterone, 19-norprogesterone, and spironolactone) of human, chicken, alligator, frog, and zebrafish full-length MRs and truncated MRs, which lacked the N-terminal domain (NTD) and DNA binding domain (DBD)...
July 3, 2018: Science Signaling
https://www.readbyqxmd.com/read/29945885/thyroid-hormone-receptor-and-err%C3%AE-coordinately-regulate-mitochondrial-fission-mitophagy-biogenesis-and-function
#9
Brijesh K Singh, Rohit A Sinha, Madhulika Tripathi, Arturo Mendoza, Kenji Ohba, Jann A C Sy, Sherwin Y Xie, Jin Zhou, Jia Pei Ho, Ching-Yi Chang, Yajun Wu, Vincent Giguère, Boon-Huat Bay, Jean-Marc Vanacker, Sujoy Ghosh, Karine Gauthier, Anthony N Hollenberg, Donald P McDonnell, Paul M Yen
Thyroid hormone receptor β1 (THRB1) and estrogen-related receptor α (ESRRA; also known as ERRα) both play important roles in mitochondrial activity. To understand their potential interactions, we performed transcriptome and ChIP-seq analyses and found that many genes that were co-regulated by both THRB1 and ESRRA were involved in mitochondrial metabolic pathways. These included oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, and β-oxidation of fatty acids. TH increased ESRRA expression and activity in a THRB1-dependent manner through the induction of the transcriptional coactivator PPARGC1A (also known as PGC1α)...
June 26, 2018: Science Signaling
https://www.readbyqxmd.com/read/29945884/the-plant-cell-wall-integrity-maintenance-and-immune-signaling-systems-cooperate-to-control-stress-responses-in-arabidopsis-thaliana
#10
Timo Engelsdorf, Nora Gigli-Bisceglia, Manikandan Veerabagu, Joseph F McKenna, Lauri Vaahtera, Frauke Augstein, Dieuwertje Van der Does, Cyril Zipfel, Thorsten Hamann
Cell walls surround all plant cells, and their composition and structure are modified in a tightly controlled, adaptive manner to meet sometimes opposing functional requirements during growth and development. The plant cell wall integrity (CWI) maintenance mechanism controls these functional modifications, as well as responses to cell wall damage (CWD). We investigated how the CWI system mediates responses to CWD in Arabidopsis thaliana CWD induced by cell wall-degrading enzymes or an inhibitor of cellulose biosynthesis elicited similar, turgor-sensitive stress responses...
June 26, 2018: Science Signaling
https://www.readbyqxmd.com/read/29945883/meg3-4-is-a-mirna-decoy-that-regulates-il-1%C3%AE-abundance-to-initiate-and-then-limit-inflammation-to-prevent-sepsis-during-lung-infection
#11
Rongpeng Li, Lizhu Fang, Qinqin Pu, Huimin Bu, Pengcheng Zhu, Zihan Chen, Min Yu, Xuefeng Li, Timothy Weiland, Arvind Bansal, Shui Qing Ye, Yuquan Wei, Jianxin Jiang, Min Wu
Long noncoding RNAs (lncRNAs) regulate gene expression. We investigated the role of lncRNAs in the inflammatory response to bacterial infection in the lungs. We identified the lncRNA MEG3 as a tissue-specific modulator of inflammatory responses during bacterial infection. Among the 10 transcript isoforms of MEG3, transcript 4 (referred to as MEG3-4) encodes the isoform with the lowest abundance in mouse lungs. Nonetheless, we found that MEG3-4 bound to the microRNA miR-138 in a competitive manner with mRNA encoding the proinflammatory cytokine interleukin-1β (IL-1β), thereby increasing IL-1β abundance and intensifying inflammatory responses to bacterial infection in alveolar macrophages and lung epithelial cells in culture and in lung tissue in mice...
June 26, 2018: Science Signaling
https://www.readbyqxmd.com/read/29921658/-parp12-suppresses-zika-virus-infection-through-parp-dependent-degradation-of-ns1-and-ns3-viral-proteins
#12
Lili Li, Hui Zhao, Ping Liu, Chunfeng Li, Natalie Quanquin, Xue Ji, Nina Sun, Peishuang Du, Cheng-Feng Qin, Ning Lu, Genhong Cheng
Zika virus infection stimulates a type I interferon (IFN) response in host cells, which suppresses viral replication. Type I IFNs exert antiviral effects by inducing the expression of hundreds of IFN-stimulated genes (ISGs). To screen for antiviral ISGs that restricted Zika virus replication, we individually knocked out 21 ISGs in A549 lung cancer cells and identified PARP12 as a strong inhibitor of Zika virus replication. Our findings suggest that PARP12 mediated the ADP-ribosylation of NS1 and NS3, nonstructural viral proteins that are involved in viral replication and modulating host defense responses...
June 19, 2018: Science Signaling
https://www.readbyqxmd.com/read/29921657/oligomerization-of-mrgc11-and-%C3%AE-opioid-receptors-in-sensory-neurons-enhances-morphine-analgesia
#13
Shao-Qiu He, Qian Xu, Vinod Tiwari, Fei Yang, Michael Anderson, Zhiyong Chen, Shaness A Grenald, Srinivasa N Raja, Xinzhong Dong, Yun Guan
The μ-opioid receptor (MOR) agonist morphine is commonly used for pain management, but it has severe adverse effects and produces analgesic tolerance. Thus, alternative ways of stimulating MOR activity are needed. We found that MrgC11, a sensory neuron-specific G protein-coupled receptor, may form heteromeric complexes with MOR. Peptide-mediated activation of MrgC11 enhanced MOR recycling by inducing coendocytosis and sorting of MOR for membrane reinsertion. MrgC11 activation also inhibited the coupling of MOR to β-arrestin-2 and enhanced the morphine-dependent inhibition of cAMP production...
June 19, 2018: Science Signaling
https://www.readbyqxmd.com/read/29921656/inhibition-of-somatosensory-mechanotransduction-by-annexin-a6
#14
Ramin Raouf, Stéphane Lolignier, Jane E Sexton, Queensta Millet, Sonia Santana-Varela, Anna Biller, Alice M Fuller, Vanessa Pereira, Jyoti S Choudhary, Mark O Collins, Stephen E Moss, Richard Lewis, Julie Tordo, Els Henckaerts, Michael Linden, John N Wood
Mechanically activated, slowly adapting currents in sensory neurons have been linked to noxious mechanosensation. The conotoxin NMB-1 (noxious mechanosensation blocker-1) blocks such currents and inhibits mechanical pain. Using a biotinylated form of NMB-1 in mass spectrometry analysis, we identified 67 binding proteins in sensory neurons and a sensory neuron-derived cell line, of which the top candidate was annexin A6, a membrane-associated calcium-binding protein. Annexin A6-deficient mice showed increased sensitivity to mechanical stimuli...
June 19, 2018: Science Signaling
https://www.readbyqxmd.com/read/29895617/regulation-of-thymocyte-trafficking-by-tagap-a-gap-domain-protein-linked-to-human-autoimmunity
#15
Jonathan S Duke-Cohan, Yuki Ishikawa, Akihiro Yoshizawa, Young-Il Choi, Chin-Nien Lee, Oreste Acuto, Stephan Kissler, Ellis L Reinherz
Multiple autoimmune pathologies are associated with single-nucleotide polymorphisms of the human gene TAGAP , which encodes TAGAP, a guanosine triphosphatase (GTPase)-activating protein. We showed in mice that Tagap-mediated signaling by the sema3E/plexin-D1 ligand-receptor complex attenuates thymocytes' adhesion to the cortex through their β1 -containing integrins. By promoting thymocyte detachment within the cortex of the thymus, Tagap-mediated signaling enabled their translocation to the medulla, which is required for continued thymic selection...
June 12, 2018: Science Signaling
https://www.readbyqxmd.com/read/29895616/a-coupled-clock-system-drives-the-automaticity-of-human-sinoatrial-nodal-pacemaker-cells
#16
Kenta Tsutsui, Oliver J Monfredi, Syevda G Sirenko-Tagirova, Larissa A Maltseva, Rostislav Bychkov, Mary S Kim, Bruce D Ziman, Kirill V Tarasov, Yelena S Tarasova, Jing Zhang, Mingyi Wang, Alexander V Maltsev, Jaclyn A Brennan, Igor R Efimov, Michael D Stern, Victor A Maltsev, Edward G Lakatta
The spontaneous rhythmic action potentials generated by the sinoatrial node (SAN), the primary pacemaker in the heart, dictate the regular and optimal cardiac contractions that pump blood around the body. Although the heart rate of humans is substantially slower than that of smaller experimental animals, current perspectives on the biophysical mechanisms underlying the automaticity of sinoatrial nodal pacemaker cells (SANCs) have been gleaned largely from studies of animal hearts. Using human SANCs, we demonstrated that spontaneous rhythmic local Ca2+ releases generated by a Ca2+ clock were coupled to electrogenic surface membrane molecules (the M clock) to trigger rhythmic action potentials, and that Ca2+ -cAMP-protein kinase A (PKA) signaling regulated clock coupling...
June 12, 2018: Science Signaling
https://www.readbyqxmd.com/read/29895615/-disruptor-residues-in-the-regulator-of-g-protein-signaling-rgs-r12-subfamily-attenuate-the-inactivation-of-g%C3%AE-subunits
#17
Ali Asli, Isra Sadiya, Meirav Avital-Shacham, Mickey Kosloff
Understanding the molecular basis of interaction specificity between RGS (regulator of G protein signaling) proteins and heterotrimeric (αβγ) G proteins would enable the manipulation of RGS-G protein interactions, explore their functions, and effectively target them therapeutically. RGS proteins are classified into four subfamilies (R4, R7, RZ, and R12) and function as negative regulators of G protein signaling by inactivating Gα subunits. We found that the R12 subfamily members RGS10 and RGS14 had lower activity than most R4 subfamily members toward the Gi subfamily member Gαo Using structure-based energy calculations with multiple Gα-RGS complexes, we identified R12-specific residues in positions that are predicted to determine the divergent activity of this subfamily...
June 12, 2018: Science Signaling
https://www.readbyqxmd.com/read/29895614/soce-mediated-by-stim-and-orai-is-essential-for-pacemaker-activity-in-the-interstitial-cells-of-cajal-in-the-gastrointestinal-tract
#18
Haifeng Zheng, Bernard T Drumm, Scott Earley, Tae Sik Sung, Sang Don Koh, Kenton M Sanders
Electrical pacemaker activity generates phasic contractions and motility patterns such as segmentation and peristalsis in the gastrointestinal tract. Pacemaker currents are generated in interstitial cells of Cajal (ICC), which release Ca2+ from intracellular stores that stimulates Ca2+ -activated Cl- channels (CaCCs) in the plasma membrane. Thus, Ca2+ stores must be maintained to sustain pacemaker activity. Store-operated Ca2+ entry (SOCE) facilitates the refilling of Ca2+ stores by a mechanism dependent upon interactions between STIM and Orai proteins...
June 12, 2018: Science Signaling
https://www.readbyqxmd.com/read/29871913/k63-linked-polyubiquitin-chains-bind-to-dna-to-facilitate-dna-damage-repair
#19
Pengda Liu, Wenjian Gan, Siyuan Su, Arthur V Hauenstein, Tian-Min Fu, Bradley Brasher, Carsten Schwerdtfeger, Anthony C Liang, Ming Xu, Wenyi Wei
Polyubiquitylation is canonically viewed as a posttranslational modification that governs protein stability or protein-protein interactions, in which distinct polyubiquitin linkages ultimately determine the fate of modified protein(s). We explored whether polyubiquitin chains have any nonprotein-related function. Using in vitro pull-down assays with synthetic materials, we found that polyubiquitin chains with the Lys63 (K63) linkage bound to DNA through a motif we called the "DNA-interacting patch" (DIP), which is composed of the adjacent residues Thr9 , Lys11 , and Glu34 Upon DNA damage, the binding of K63-linked polyubiquitin chains to DNA enhanced the recruitment of repair factors through their interaction with an Ile44 patch in ubiquitin to facilitate DNA repair...
June 5, 2018: Science Signaling
https://www.readbyqxmd.com/read/29871912/the-channel-kinase-trpm7-regulates-antigen-gathering-and-internalization-in-b-cells
#20
Mithunah Krishnamoorthy, Laabiah Wasim, Fathima Hifza Mohamed Buhari, Tiantian Zhao, Trisha Mahtani, Josephine Ho, Sohee Kang, Francina Deason-Towne, Anne-Laure Perraud, Carsten Schmitz, Bebhinn Treanor
Members of the transient receptor potential (TRP) family of ion channels are cellular sensors involved in numerous physiological and pathological processes. We identified the TRP subfamily M member 7 (TRPM7) channel-kinase as a previously uncharacterized regulator of B cell activation. We showed that TRPM7 played a critical role in the early events of B cell activation through both its ion channel and kinase functions. DT40 B cells deficient in TRPM7 or expressing a kinase-deficient mutant of TRPM7 showed defective gathering of antigen and prolonged B cell receptor (BCR) signaling...
June 5, 2018: Science Signaling
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