Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy
In this study, we isolated three bacterial species—Bifidobacterium pseudolongum, Lactobacillus johnsonii, and Olsenella species—that significantly enhanced efficacy of immune checkpoint inhibitors in four mouse models of cancer. We found that intestinal B. pseudolongum modulated enhanced immunotherapy response through production of the metabolite inosine. Decreased gut barrier function induced by immunotherapy increased systemic translocation of inosine and activated antitumor T cells. The effect of inosine was dependent on T cell expression of the adenosine A2A receptor and required costimulation. Collectively...
Source: ScienceNOW - September 17, 2020 Category: Science Authors: Mager, L. F., Burkhard, R., Pett, N., Cooke, N. C. A., Brown, K., Ramay, H., Paik, S., Stagg, J., Groves, R. A., Gallo, M., Lewis, I. A., Geuking, M. B., McCoy, K. D. Tags: Immunology, Medicine, Diseases reports Source Type: news

The gut as a hidden source of sepsis
From the initial hypothesis considering 30 years ago the gut as the " motor " of multiple organ failure (MOF) related to an induced hyperpermeability leading to bacterial translocation into the systemic circulation, the reality becomes significantly more complex. The gut contains three interplaying components - the epithelium, the microbiome, and the immune system - that have to cooperate to maintain two opposite function: adsorption of nutrients and maintenance of a barrier to prevent the crossing of intraluminal microbes or their products to avoid host response. Many critical illnesses are altering such a funct...
Source: Current Awareness Service for Health (CASH) - September 3, 2020 Category: Consumer Health News Source Type: news

Degradation of 5hmC-marked stalled replication forks by APE1 causes genomic instability
Synthetic lethality between poly(ADP-ribose) polymerase (PARP) inhibition and BRCA deficiency is exploited to treat breast and ovarian tumors. However, resistance to PARP inhibitors (PARPis) is common. To identify potential resistance mechanisms, we performed a genome-wide RNAi screen in BRCA2-deficient mouse embryonic stem cells and validation in KB2P1.21 mouse mammary tumor cells. We found that resistance to multiple PARPi emerged with reduced expression of TET2 (ten-eleven translocation), which promotes DNA demethylation by oxidizing 5-methylcytosine (5mC) to 5-hydroxymethycytosine (5hmC) and other products. TET2 knockd...
Source: Signal Transduction Knowledge Environment - August 18, 2020 Category: Science Authors: Kharat, S. S., Ding, X., Swaminathan, D., Suresh, A., Singh, M., Sengodan, S. K., Burkett, S., Marks, H., Pamala, C., He, Y., Fox, S. D., Buehler, E. C., Muegge, K., Martin, S. E., Sharan, S. K. Tags: STKE Research Articles Source Type: news

Cognitive map-based navigation in wild bats revealed by a new high-throughput tracking system
Seven decades of research on the "cognitive map," the allocentric representation of space, have yielded key neurobiological insights, yet field evidence from free-ranging wild animals is still lacking. Using a system capable of tracking dozens of animals simultaneously at high accuracy and resolution, we assembled a large dataset of 172 foraging Egyptian fruit bats comprising>18 million localizations collected over 3449 bat-nights across 4 years. Detailed track analysis, combined with translocation experiments and exhaustive mapping of fruit trees, revealed that wild bats seldom exhibit random search but inste...
Source: ScienceNOW - July 9, 2020 Category: Science Authors: Toledo, S., Shohami, D., Schiffner, I., Lourie, E., Orchan, Y., Bartan, Y., Nathan, R. Tags: Ecology reports Source Type: news

A PI3K- and GTPase-independent Rac1-mTOR mechanism mediates MET-driven anchorage-independent cell growth but not migration
Receptor tyrosine kinases (RTKs) are often overexpressed or mutated in cancers and drive tumor growth and metastasis. In the current model of RTK signaling, including that of MET, downstream phosphatidylinositol 3-kinase (PI3K) mediates both cell proliferation and cell migration, whereas the small guanosine triphosphatase (GTPase) Rac1 mediates cell migration. However, in cultured NIH3T3 and glioblastoma cells, we found that class I PI3K mediated oncogenic MET–induced cell migration but not anchorage-independent growth. In contrast, Rac1 regulated both processes in distinct ways. Downstream of PI3K, Rac1 mediated cel...
Source: Signal Transduction Knowledge Environment - June 23, 2020 Category: Science Authors: Hervieu, A., Heuss, S. F., Zhang, C., Barrow-McGee, R., Joffre, C., Menard, L., Clarke, P. A., Kermorgant, S. Tags: STKE Research Articles Source Type: news

Nutrient transporter translocation to the plasma membrane via Golgi bypass in Aspergillus nidulans
Conference abstracts (Source: The Aspergillus Website - updates)
Source: The Aspergillus Website - updates - June 20, 2020 Category: Respiratory Medicine Authors: MeganB Source Type: news

IGF-1 receptor activity in the Golgi of migratory cancer cells depends on adhesion-dependent phosphorylation of Tyr1250 and Tyr1251
Although insulin-like growth factor 1 (IGF-1) signaling promotes tumor growth and cancer progression, therapies that target the IGF-1 receptor (IGF-1R) have shown poor clinical efficacy. To address IGF-1R activity in cancer cells and how it differs from that of the closely related insulin receptor (IR), we focused on two tyrosines in the IGF-1R C-terminal tail that are not present in the IR and are essential for IGF-1–mediated cancer cell survival, migration, and tumorigenic growth. We found that Tyr1250 and Tyr1251 (Tyr1250/1251) were autophosphorylated in a cell adhesion–dependent manner. To investigate the c...
Source: Signal Transduction Knowledge Environment - May 26, 2020 Category: Science Authors: Rieger, L., OShea, S., Godsmark, G., Stanicka, J., Kelly, G., OConnor, R. Tags: STKE Research Articles Source Type: news

Diacylglycerol kinase {zeta} promotes actin cytoskeleton remodeling and mechanical forces at the B cell immune synapse
Diacylglycerol kinases (DGKs) limit antigen receptor signaling in immune cells by consuming the second messenger diacylglycerol (DAG) to generate phosphatidic acid (PA). Here, we showed that DGK promotes lymphocyte function–associated antigen 1 (LFA-1)–mediated adhesion and F-actin generation at the immune synapse of B cells with antigen-presenting cells (APCs), mostly in a PA-dependent manner. Measurement of single-cell mechanical force generation indicated that DGK-deficient B cells exerted lower forces at the immune synapse than did wild-type B cells. Nonmuscle myosin activation and translocation of the micr...
Source: Signal Transduction Knowledge Environment - April 14, 2020 Category: Science Authors: Merino-Cortes, S. V., Gardeta, S. R., Roman-Garcia, S., Martinez-Riano, A., Pineau, J., Liebana, R., Merida, I., Dumenil, A.-M. L., Pierobon, P., Husson, J., Alarcon, B., Carrasco, Y. R. Tags: STKE Research Articles Source Type: news

Noncanonical STAT1 phosphorylation expands its transcriptional activity into promoting LPS-induced IL-6 and IL-12p40 production
The lipopolysaccharide (LPS)–induced endocytosis of Toll-like receptor 4 (TLR4) is an essential step in the production of interferon-β (IFN-β), which activates the transcription of antiviral response genes by STAT1 phosphorylated at Tyr701. Here, we showed that STAT1 regulated proinflammatory cytokine production downstream of TLR4 endocytosis independently of IFN-β signaling and the key proinflammatory regulator NF-B. In human macrophages, TLR4 endocytosis activated a noncanonical phosphorylation of STAT1 at Thr749, which subsequently promoted the production of interleukin-6 (IL-6) and IL-12p40 through...
Source: Signal Transduction Knowledge Environment - March 24, 2020 Category: Science Authors: Metwally, H., Tanaka, T., Li, S., Parajuli, G., Kang, S., Hanieh, H., Hashimoto, S., Chalise, J. P., Gemechu, Y., Standley, D. M., Kishimoto, T. Tags: STKE Research Articles Source Type: news

Improving success of giraffe translocations
(Penn State) In two new studies, an international team of researchers identifies the ideal composition of a group of giraffes to be translocated for conservation purposes and provides guidelines for all aspects of the translocation process. (Source: EurekAlert! - Biology)
Source: EurekAlert! - Biology - March 19, 2020 Category: Biology Source Type: news

PTPN22 phosphorylation acts as a molecular rheostat for the inhibition of TCR signaling
The hematopoietic-specific protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is encoded by a major autoimmunity risk gene. PTPN22 inhibits T cell activation by dephosphorylating substrates involved in proximal T cell receptor (TCR) signaling. Here, we found by mass spectrometry that PTPN22 was phosphorylated at Ser751 by PKCα in Jurkat and primary human T cells activated with phorbol ester/ionomycin or antibodies against CD3/CD28. The phosphorylation of PTPN22 at Ser751 prolonged its half-life by inhibiting K48-linked ubiquitination and impairing recruitment of the phosphatase to the plasma membrane, which is...
Source: Signal Transduction Knowledge Environment - March 17, 2020 Category: Science Authors: Yang, S., Svensson, M. N. D., Harder, N. H. O., Hsieh, W.-C., Santelli, E., Kiosses, W. B., Moresco, J. J., Yates, J. R., King, C. C., Liu, L., Stanford, S. M., Bottini, N. Tags: STKE Research Articles Source Type: news

Clostridium perfringens enterotoxin induces claudin-4 to activate YAP in oral squamous cell
(Impact Journals LLC) Oncotarget Volume 11, Issue 4: Treatment of human oral squamous cell carcinoma cell lines HSC3 and HSC4 with Clostridium perfringens enterotoxin, induced CLDN4 nuclear translocation to enhance epithelial-mesenchymal transition, stemness, cell proliferation, and invasive ability. (Source: EurekAlert! - Cancer)
Source: EurekAlert! - Cancer - February 4, 2020 Category: Cancer & Oncology Source Type: news

The parkin-coregulated gene product PACRG promotes TNF signaling by stabilizing LUBAC
The Parkin-coregulated gene (PACRG), which encodes a protein of unknown function, shares a bidirectional promoter with Parkin (PRKN), which encodes an E3 ubiquitin ligase. Because PRKN is important in mitochondrial quality control and protection against stress, we tested whether PACRG also affected these pathways in various cultured human cell lines and in mouse embryonic fibroblasts. PACRG did not play a role in mitophagy but did play a role in tumor necrosis factor (TNF) signaling. Similarly to Parkin, PACRG promoted nuclear factor B (NF-B) activation in response to TNF. TNF-induced nuclear translocation of the NF-B subu...
Source: Signal Transduction Knowledge Environment - February 4, 2020 Category: Science Authors: Meschede, J., Sadic, M., Furthmann, N., Miedema, T., Sehr, D. A., Müller-Rischart, A. K., Bader, V., Berlemann, L. A., Pilsl, A., Schlierf, A., Barkovits, K., Kachholz, B., Rittinger, K., Ikeda, F., Marcus, K., Schaefer, L., Tatzelt, J., Winklhofe Tags: STKE Research Articles Source Type: news

Dynamic palmitoylation controls the microdomain localization of the DKK1 receptors CKAP4 and LRP6
Dickkopf1 (DKK1) was originally identified as an antagonist of Wnt signaling that binds to and induces the clathrin-mediated endocytosis of the Wnt coreceptors low-density lipoprotein receptor–related proteins 5 and 6 (LRP5/6). DKK1 also binds to cytoskeleton-associated protein 4 (CKAP4), which was originally identified as an endoplasmic reticulum (ER) protein but also functions at the plasma membrane as a receptor for various ligands. The DKK1-CKAP4 pathway is activated in several human cancers and promotes cell proliferation by activating signaling through the kinases PI3K and AKT. We found that both CKAP4 and LRP6...
Source: Signal Transduction Knowledge Environment - November 19, 2019 Category: Science Authors: Sada, R., Kimura, H., Fukata, Y., Fukata, M., Yamamoto, H., Kikuchi, A. Tags: STKE Research Articles Source Type: news

Structure of the RSC complex bound to the nucleosome
The RSC complex remodels chromatin structure and regulates gene transcription. We used cryo–electron microscopy to determine the structure of yeast RSC bound to the nucleosome. RSC is delineated into the adenosine triphosphatase motor, the actin-related protein module, and the substrate recruitment module (SRM). RSC binds the nucleosome mainly through the motor, with the auxiliary subunit Sfh1 engaging the H2A-H2B acidic patch to enable nucleosome ejection. SRM is organized into three substrate-binding lobes poised to bind their respective nucleosomal epitopes. The relative orientations of the SRM and the motor on th...
Source: ScienceNOW - November 14, 2019 Category: Science Authors: Ye, Y., Wu, H., Chen, K., Clapier, C. R., Verma, N., Zhang, W., Deng, H., Cairns, B. R., Gao, N., Chen, Z. Tags: Biochemistry r-articles Source Type: news

Translocation of TRPV4-PI3K{gamma} complexes to the plasma membrane drives myofibroblast transdifferentiation
Myofibroblasts are key contributors to pathological fibrotic conditions of several major organs. The transdifferentiation of fibroblasts into myofibroblasts requires both a mechanical signal and transforming growth factor–β (TGF-β) signaling. The cation channel transient receptor potential vanilloid 4 (TRPV4) is a critical mediator of myofibroblast transdifferentiation and in vivo fibrosis through its mechanosensitivity to extracellular matrix stiffness. Here, we showed that TRPV4 promoted the transdifferentiation of human and mouse lung fibroblasts through its interaction with phosphoinositide 3-kinase (PI...
Source: Signal Transduction Knowledge Environment - November 12, 2019 Category: Science Authors: Grove, L. M., Mohan, M. L., Abraham, S., Scheraga, R. G., Southern, B. D., Crish, J. F., Naga Prasad, S. V., Olman, M. A. Tags: STKE Research Articles Source Type: news

Structural basis for the docking of mTORC1 on the lysosomal surface
The mTORC1 (mechanistic target of rapamycin complex 1) protein kinase regulates growth in response to nutrients and growth factors. Nutrients promote its translocation to the lysosomal surface, where its Raptor subunit interacts with the Rag guanosine triphosphatase (GTPase)–Ragulator complex. Nutrients switch the heterodimeric Rag GTPases among four different nucleotide-binding states, only one of which (RagA/B•GTP–RagC/D•GDP) permits mTORC1 association. We used cryo–electron microscopy to determine the structure of the supercomplex of Raptor with Rag-Ragulator at a resolution of 3.2 angstroms....
Source: ScienceNOW - October 24, 2019 Category: Science Authors: Rogala, K. B., Gu, X., Kedir, J. F., Abu-Remaileh, M., Bianchi, L. F., Bottino, A. M. S., Dueholm, R., Niehaus, A., Overwijn, D., Fils, A.-C. P., Zhou, S. X., Leary, D., Laqtom, N. N., Brignole, E. J., Sabatini, D. M. Tags: Biochemistry r-articles Source Type: news

Structural basis for client recognition and activity of Hsp40 chaperones
Hsp70 and Hsp40 chaperones work synergistically in a wide range of biological processes including protein synthesis, membrane translocation, and folding. We used nuclear magnetic resonance spectroscopy to determine the solution structure and dynamic features of an Hsp40 in complex with an unfolded client protein. Atomic structures of the various binding sites in the client complexed to the binding domains of the Hsp40 reveal the recognition pattern. Hsp40 engages the client in a highly dynamic fashion using a multivalent binding mechanism that alters the folding properties of the client. Different Hsp40 family members have...
Source: ScienceNOW - September 19, 2019 Category: Science Authors: Jiang, Y., Rossi, P., Kalodimos, C. G. Tags: Biochemistry reports Source Type: news

Tumor-derived TGF-{beta} inhibits mitochondrial respiration to suppress IFN-{gamma} production by human CD4+ T cells
Transforming growth factor–β (TGF-β) is produced by tumors, and increased amounts of this cytokine in the tumor microenvironment and serum are associated with poor patient survival. TGF-β–mediated suppression of antitumor T cell responses contributes to tumor growth and survival. However, TGF-β also has tumor-suppressive activity; thus, dissecting cell type–specific molecular effects may inform therapeutic strategies targeting this cytokine. Here, using human peripheral and tumor-associated lymphocytes, we investigated how tumor-derived TGF-β suppresses a key antitumor function of...
Source: Signal Transduction Knowledge Environment - September 17, 2019 Category: Science Authors: Dimeloe, S., Gubser, P., Loeliger, J., Frick, C., Develioglu, L., Fischer, M., Marquardsen, F., Bantug, G. R., Thommen, D., Lecoultre, Y., Zippelius, A., Langenkamp, A., Hess, C. Tags: STKE Research Articles Source Type: news

Cryo-EM structures capture the transport cycle of the P4-ATPase flippase
In eukaryotic membranes, type IV P-type adenosine triphosphatases (P4-ATPases) mediate the translocation of phospholipids from the outer to the inner leaflet and maintain lipid asymmetry, which is critical for membrane trafficking and signaling pathways. Here, we report the cryo–electron microscopy structures of six distinct intermediates of the human ATP8A1-CDC50a heterocomplex at resolutions of 2.6 to 3.3 angstroms, elucidating the lipid translocation cycle of this P4-ATPase. ATP-dependent phosphorylation induces a large rotational movement of the actuator domain around the phosphorylation site in the phosphorylati...
Source: ScienceNOW - September 12, 2019 Category: Science Authors: Hiraizumi, M., Yamashita, K., Nishizawa, T., Nureki, O. Tags: Biochemistry r-articles Source Type: news

Structure and conformational plasticity of the intact Thermus thermophilus V/A-type ATPase
V (vacuolar)/A (archaeal)-type adenosine triphosphatases (ATPases), found in archaea and eubacteria, couple ATP hydrolysis or synthesis to proton translocation across the plasma membrane using the rotary-catalysis mechanism. They belong to the V-type ATPase family, which differs from the mitochondrial/chloroplast F-type ATP synthases in overall architecture. We solved cryo–electron microscopy structures of the intact Thermus thermophilus V/A-ATPase, reconstituted into lipid nanodiscs, in three rotational states and two substates. These structures indicate substantial flexibility between V1 and Vo in a working enzyme,...
Source: ScienceNOW - August 22, 2019 Category: Science Authors: Zhou, L., Sazanov, L. A. Tags: Biochemistry, Online Only r-articles Source Type: news

Nuclear hnRNPA2B1 initiates and amplifies the innate immune response to DNA viruses
We report that heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) recognizes pathogenic DNA and amplifies interferon-α/β (IFN-α/β) production. Upon DNA virus infection, nuclear-localized hnRNPA2B1 senses viral DNA, homodimerizes, and is then demethylated at arginine-226 by the arginine demethylase JMJD6. This results in hnRNPA2B1 translocation to the cytoplasm where it activates the TANK-binding kinase 1–interferon regulatory factor 3 (TBK1–IRF3) pathway, leading to IFN-α/β production. Additionally, hnRNPA2B1 facilitates N6-methyladenosine (m6A) modification and nucleocyto...
Source: ScienceNOW - August 15, 2019 Category: Science Authors: Wang, L., Wen, M., Cao, X. Tags: Immunology, Molecular Biology, Online Only r-articles Source Type: news

Structure of the Cdc48 segregase in the act of unfolding an authentic substrate
The cellular machine Cdc48 functions in multiple biological pathways by segregating its protein substrates from a variety of stable environments such as organelles or multi-subunit complexes. Despite extensive studies, the mechanism of Cdc48 has remained obscure, and its reported structures are inconsistent with models of substrate translocation proposed for other AAA+ ATPases (adenosine triphosphatases). Here, we report a 3.7-angstrom–resolution structure of Cdc48 in complex with an adaptor protein and a native substrate. Cdc48 engages substrate by adopting a helical configuration of substrate-binding residues that ...
Source: ScienceNOW - August 1, 2019 Category: Science Authors: Cooney, I., Han, H., Stewart, M. G., Carson, R. H., Hansen, D. T., Iwasa, J. H., Price, J. C., Hill, C. P., Shen, P. S. Tags: Biochemistry reports Source Type: news

Understanding social structure is important to rewilding
(San Diego Zoo Global) Increasing the success of wildlife translocations is critical, given the escalating global threats to wildlife. The study highlights the influence of a species' social structure on translocation success, and it provides a template for incorporating social information in the rehabilitation and release planning process. Using elephants as a model, the study highlights the need to include animal social structure as an integral part of conservation plans, in order to assure better animal welfare and program success. (Source: EurekAlert! - Social and Behavioral Science)
Source: EurekAlert! - Social and Behavioral Science - June 13, 2019 Category: International Medicine & Public Health Source Type: news

Flotillin-mediated endocytosis and ALIX-syntenin-1-mediated exocytosis protect the cell membrane from damage caused by necroptosis
Necroptosis is a form of regulated necrosis that is implicated in various human diseases including Alzheimer’s disease. Necroptosis requires the translocation of the pseudokinase MLKL from the cytosol to the plasma membrane after its phosphorylation by the kinase RIPK3. Using protein cross-linking followed by affinity purification, we detected the lipid raft–associated proteins flotillin-1 and flotillin-2 and the ESCRT-associated proteins ALIX and syntenin-1 in membrane-localized MLKL immunoprecipitates. Phosphorylated MLKL was removed from membranes through either flotillin-mediated endocytosis followed by lys...
Source: Signal Transduction Knowledge Environment - May 28, 2019 Category: Science Authors: Fan, W., Guo, J., Gao, B., Zhang, W., Ling, L., Xu, T., Pan, C., Li, L., Chen, S., Wang, H., Zhang, J., Wang, X. Tags: STKE Research Articles Source Type: news

Miro2 is a Parkin receptor for selective removal of damaged mitochondria
(Science China Press) Defects in mitophagy are linked to a variety of human diseases including Parkinson's and cardiac disorders. At present, how the damaged mitochondria are selectively recognized and targeted by Parkin is not fully understood. Miro2, a mitochondrial outer membrane protein, has been identified as a platform for Parkin translocation to damaged mitochondria. Miro2 senses both the depolarization and the Ca2+ release from mitochondria to ensure that only damaged mitochondria are targeted by Parkin for mitophagic clearance. (Source: EurekAlert! - Biology)
Source: EurekAlert! - Biology - May 16, 2019 Category: Biology Source Type: news

p62 and Nrf2 are essential for exercise-mediated enhancement of antioxidant protein in muscle
(Nagoya City University) Regular exercise prevents oxidative stress-induced muscle wasting, at least partially by improving the antioxidant defense system. In the present study, we found that regular endurance exercise enhances the expression of p62/SQSTM1 (p62) and its phosphorylation at Ser 351 thereby dissociating nuclear factor erythroid 2-related factor 2 (Nrf2) from Keap1, which results in increased Nrf2 nuclear translocation and DNA binding activity. These findings suggest that Ser 351 phosphorylation of p62 plays a critical role in this regulation. (Source: EurekAlert! - Biology)
Source: EurekAlert! - Biology - April 25, 2019 Category: Biology Source Type: news

TRPV1 promotes opioid analgesia during inflammation
Pain and inflammation are inherently linked responses to injury, infection, or chronic diseases. Given that acute inflammation in humans or mice enhances the analgesic properties of opioids, there is much interest in determining the inflammatory transducers that prime opioid receptor signaling in primary afferent nociceptors. Here, we found that activation of the transient receptor potential vanilloid type 1 (TRPV1) channel stimulated a mitogen-activated protein kinase (MAPK) signaling pathway that was accompanied by the shuttling of the scaffold protein β-arrestin2 to the nucleus. The nuclear translocation of β-...
Source: Signal Transduction Knowledge Environment - April 2, 2019 Category: Science Authors: Basso, L., Aboushousha, R., Fan, C. Y., Iftinca, M., Melo, H., Flynn, R., Agosti, F., Hollenberg, M. D., Thompson, R., Bourinet, E., Trang, T., Altier, C. Tags: STKE Research Articles Source Type: news

Translocation of bighorn sheep in Arizona has positive genetic outcomes
(University of Wyoming) Research shows it is possible to re-establish bighorn sheep populations without a reduction of genetic diversity over a short period and without erosion of ancestral lineage. (Source: EurekAlert! - Medicine and Health)
Source: EurekAlert! - Medicine and Health - March 6, 2019 Category: International Medicine & Public Health Source Type: news

Immunometabolism regulates TCR recycling and iNKT cell functions
Invariant natural killer T (iNKT) cells are innate-like T lymphocytes that express an invariant T cell receptor (TCR), which recognizes glycolipid antigens presented on CD1d molecules. These cells are phenotypically and functionally distinct from conventional T cells. When we characterized the metabolic activity of iNKT cells, consistent with their activated phenotype, we found that they had much less mitochondrial respiratory capacity but increased glycolytic activity in comparison to naìˆve conventional CD4+ T cells. After TCR engagement, iNKT cells further increased aerobic glycolysis, which was important for the expre...
Source: Signal Transduction Knowledge Environment - February 26, 2019 Category: Science Authors: Fu, S., Zhu, S., Tian, C., Bai, S., Zhang, J., Zhan, C., Xie, D., Wang, L., Li, Z., Li, J., Zhang, H., Zhou, R., Tian, Z., Xu, T., Bai, L. Tags: STKE Research Articles Source Type: news

Structure of the posttranslational Sec protein-translocation channel complex from yeast
The Sec61 protein-conducting channel mediates transport of many proteins, such as secretory proteins, across the endoplasmic reticulum (ER) membrane during or after translation. Posttranslational transport is enabled by two additional membrane proteins associated with the channel, Sec63 and Sec62, but its mechanism is poorly understood. We determined a structure of the Sec complex (Sec61-Sec63-Sec71-Sec72) from Saccharomyces cerevisiae by cryo–electron microscopy (cryo-EM). The structure shows that Sec63 tightly associates with Sec61 through interactions in cytosolic, transmembrane, and ER-luminal domains, prying ope...
Source: ScienceNOW - January 3, 2019 Category: Science Authors: Itskanov, S., Park, E. Tags: Biochemistry reports Source Type: news

Restricting mitochondrial GRK2 post-ischemia confers cardioprotection by reducing myocyte death and maintaining glucose oxidation
Increased abundance of GRK2 [G protein–coupled receptor (GPCR) kinase 2] is associated with poor cardiac function in heart failure patients. In animal models, GRK2 contributes to the pathogenesis of heart failure after ischemia-reperfusion (IR) injury. In addition to its role in down-regulating activated GPCRs, GRK2 also localizes to mitochondria both basally and post-IR injury, where it regulates cellular metabolism. We previously showed that phosphorylation of GRK2 at Ser670 is essential for the translocation of GRK2 to the mitochondria of cardiomyocytes post-IR injury in vitro and that this localization promotes c...
Source: Signal Transduction Knowledge Environment - December 11, 2018 Category: Science Authors: Sato, P. Y., Chuprun, J. K., Grisanti, L. A., Woodall, M. C., Brown, B. R., Roy, R., Traynham, C. J., Ibetti, J., Lucchese, A. M., Yuan, A., Drosatos, K., Tilley, D. G., Gao, E., Koch, W. J. Tags: STKE Research Articles Source Type: news

The {beta}4 subunit of Cav1.2 channels is required for an optimal interferon response in cardiac muscle cells
The auxiliary β4 subunit of the cardiac Cav1.2 channel plays a poorly understood role in gene transcription. Here, we characterized the regulatory effects of the β4 subunit in H9c2 rat cardiac cells on the abundances of Ifnb mRNA [which encodes interferon-β (IFN-β)] and of the IFN-β–related genes Ddx58, Ifitm3, Irf7, Stat2, Ifih1, and Mx1, as well as on the abundances of the antiviral proteins DDX58, IRF7, STAT2, and IFITM3. Knocking down the β4 subunit in H9c2 cells reduced the expression of IFN-β–stimulated genes. In response to inhibition of the kinase JAK1, the abundances ...
Source: Signal Transduction Knowledge Environment - December 11, 2018 Category: Science Authors: Tammineni, E. R., Carrillo, E. D., Soto-Acosta, R., Angel-Ambrocio, A. H., Garcia, M. C., Bautista-Carbajal, P., del Angel, R. M., Sanchez, J. A. Tags: STKE Research Articles Source Type: news

Substrate-engaged 26S proteasome structures reveal mechanisms for ATP-hydrolysis-driven translocation
The 26S proteasome is the primary eukaryotic degradation machine and thus is critically involved in numerous cellular processes. The heterohexameric adenosine triphosphatase (ATPase) motor of the proteasome unfolds and translocates targeted protein substrates into the open gate of a proteolytic core while a proteasomal deubiquitinase concomitantly removes substrate-attached ubiquitin chains. However, the mechanisms by which ATP hydrolysis drives the conformational changes responsible for these processes have remained elusive. Here we present the cryo–electron microscopy structures of four distinct conformational stat...
Source: ScienceNOW - November 29, 2018 Category: Science Authors: de la Pena, A. H., Goodall, E. A., Gates, S. N., Lander, G. C., Martin, A. Tags: Biochemistry, Online Only r-articles Source Type: news

Erratum: Vol. 67, No. 42
In the report " Translocation of a Stray Cat Infected with Rabies from North Carolina to a Terrestrial Rabies-Free County in Ohio, 2017, " (Source: CDC Morbidity and Mortality Weekly Report)
Source: CDC Morbidity and Mortality Weekly Report - November 8, 2018 Category: American Health Tags: Breastfeeding Health Departments Immunization Immunization Schedules Infant Health Meningitis MMWR Morbidity & Mortality Weekly Report Polio (poliomyelitis) Polio Vaccination Valley Fever (Coccidioidomycosis) Infant Feeding Source Type: news

Leaky gut biomarkers in depression and suicidal behavior - Ohlsson L, Gustafsson A, Lavant E, Suneson K, Brundin L, Westrin A, Ljunggren L, Lindqvist D.
OBJECTIVE: Inflammation is associated with major depressive disorder (MDD) and suicidal behavior. According to the "leaky gut hypothesis", increased intestinal permeability may contribute to this relationship via bacterial translocation across enterocytes.... (Source: SafetyLit)
Source: SafetyLit - October 27, 2018 Category: International Medicine & Public Health Tags: Suicide and Self-Harm Source Type: news

Translocation of a Stray Cat Infected with Rabies from North Carolina to a Terrestrial Rabies-Free County in Ohio, 2017
On July 24, 2017, the Ohio Department of Health was notified of a positive rabies test result from a domestic cat in Summit County, a county considered free from terrestrial rabies. (Source: CDC Morbidity and Mortality Weekly Report)
Source: CDC Morbidity and Mortality Weekly Report - October 25, 2018 Category: American Health Tags: MMWR Morbidity & Mortality Weekly Report Outbreaks Rabies Rabies Vaccine Swine Influenza Variant Influenza Source Type: news

Sphingosine 1-phosphate stimulates eyelid closure in the developing rat by stimulating EGFR signaling
In many mammals, the eyelids migrate over the eye and fuse during embryogenesis to protect the cornea from damage during birth and early life. Loss-of-function mutations affecting the epidermal growth factor receptor (EGFR) signaling pathway cause an eyes-open-at-birth (EOB) phenotype in rodents. We identified an insertional mutation in Spinster homolog 2 (Spns2) in a strain of transgenic rats exhibiting the EOB phenotype. Spns2, a sphingosine 1-phosphate (S1P) transporter that releases S1P from cells, was enriched at the tip of developing eyelids in wild-type rat embryos. Spns2 expression or treatment with S1P or any one ...
Source: Signal Transduction Knowledge Environment - October 23, 2018 Category: Science Authors: Bian, G., Yu, C., Liu, L., Fang, C., Chen, K., Ren, P., Zhang, Q., Liu, F., Zhang, K., Xue, Q., Xiang, J., Guo, H., Song, J., Zhao, Y., Wu, W., Chung, S. K., Sun, R., Ju, G., Wang, J. Tags: STKE Research Articles Source Type: news

Heredity matters: Ancestral protease functions as protein import motor in chloroplasts
(Osaka University) Japanese researchers identified a large novel protein complex in the inner chloroplast membrane that functions as a motor to import proteins into the chloroplast. Components of the complex evolved from a protein of the endosymbiont cyanobacterium-like ancestor of chloroplasts that lost its protein-degrading function but retained its motor ability. These findings solve a longstanding mystery surrounding this protein translocation system that uniquely evolved in photosynthetic eukaryotes. (Source: EurekAlert! - Biology)
Source: EurekAlert! - Biology - October 22, 2018 Category: Biology Source Type: news

Systemic control of legume susceptibility to rhizobial infection by a mobile microRNA
Nitrogen-fixing root nodules on legumes result from two developmental processes, bacterial infection and nodule organogenesis. To balance symbiosis and plant growth, legume hosts restrict nodule numbers through an inducible autoregulatory process. Here, we present a mechanism where repression of a negative regulator ensures symbiotic susceptibility of uninfected roots of the host Lotus japonicus. We show that microRNA miR2111 undergoes shoot-to-root translocation to control rhizobial infection through posttranscriptional regulation of the symbiosis suppressor TOO MUCH LOVE in roots. miR2111 maintains a susceptible default ...
Source: ScienceNOW - October 11, 2018 Category: Science Authors: Tsikou, D., Yan, Z., Holt, D. B., Abel, N. B., Reid, D. E., Madsen, L. H., Bhasin, H., Sexauer, M., Stougaard, J., Markmann, K. Tags: Botany, Cell Biology reports Source Type: news

Structure and dynamics of the yeast SWR1-nucleosome complex
The yeast SWR1 complex exchanges histone H2A in nucleosomes with Htz1 (H2A.Z in humans). The cryo–electron microscopy structure of the SWR1 complex bound to a nucleosome at 3.6-angstrom resolution reveals details of the intricate interactions between components of the SWR1 complex and its nucleosome substrate. Interactions between the Swr1 motor domains and the DNA wrap at superhelical location 2 distort the DNA, causing a bulge with concomitant translocation of the DNA by one base pair, coupled to conformational changes of the histone core. Furthermore, partial unwrapping of the DNA from the histone core takes place...
Source: ScienceNOW - October 11, 2018 Category: Science Authors: Willhoft, O., Ghoneim, M., Lin, C.-L., Chua, E. Y. D., Wilkinson, M., Chaban, Y., Ayala, R., McCormack, E. A., Ocloo, L., Rueda, D. S., Wigley, D. B. Tags: Biochemistry, Online Only r-articles Source Type: news

Preassembled GPCR signaling complexes mediate distinct cellular responses to ultralow ligand concentrations
G protein–coupled receptors (GPCRs) are the largest class of cell surface signaling proteins, participate in nearly all physiological processes, and are the targets of 30% of marketed drugs. Typically, nanomolar to micromolar concentrations of ligand are used to activate GPCRs in experimental systems. We detected GPCR responses to a wide range of ligand concentrations, from attomolar to millimolar, by measuring GPCR-stimulated production of cyclic adenosine monophosphate (cAMP) with high spatial and temporal resolution. Mathematical modeling showed that femtomolar concentrations of ligand activated, on average, 40% o...
Source: Signal Transduction Knowledge Environment - October 9, 2018 Category: Science Authors: Civciristov, S., Ellisdon, A. M., Suderman, R., Pon, C. K., Evans, B. A., Kleifeld, O., Charlton, S. J., Hlavacek, W. S., Canals, M., Halls, M. L. Tags: STKE Research Articles Source Type: news

CDK12-mediated transcriptional regulation of noncanonical NF-{kappa}B components is essential for signaling
Members of the family of nuclear factor B (NF-B) transcription factors are critical for multiple cellular processes, including regulating innate and adaptive immune responses, cell proliferation, and cell survival. Canonical NF-B complexes are retained in the cytoplasm by the inhibitory protein IBα, whereas noncanonical NF-B complexes are retained by p100. Although activation of canonical NF-B signaling through the IBα kinase complex is well studied, few regulators of the NF-B–inducing kinase (NIK)–dependent processing of noncanonical p100 to p52 and the subsequent nuclear translocation of p52 have ...
Source: Signal Transduction Knowledge Environment - July 31, 2018 Category: Science Authors: Henry, K. L., Kellner, D., Bajrami, B., Anderson, J. E., Beyna, M., Bhisetti, G., Cameron, T., Capacci, A. G., Bertolotti-Ciarlet, A., Feng, J., Gao, B., Hopkins, B., Jenkins, T., Li, K., May-Dracka, T., Murugan, P., Wei, R., Zeng, W., Allaire, N., Buckle Tags: STKE Research Articles Source Type: news

Regulation of thymocyte trafficking by Tagap, a GAP domain protein linked to human autoimmunity
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. Tagap physically interacted with the cytoplasmic domain of p...
Source: Signal Transduction Knowledge Environment - June 12, 2018 Category: Science Authors: Duke-Cohan, J. S., Ishikawa, Y., Yoshizawa, A., Choi, Y.-I., Lee, C.-N., Acuto, O., Kissler, S., Reinherz, E. L. Tags: STKE Research Articles Source Type: news

High-resolution cryo-EM analysis of the yeast ATP synthase in a lipid membrane
Mitochondrial adenosine triphosphate (ATP) synthase comprises a membrane embedded Fo motor that rotates to drive ATP synthesis in the F1 subunit. We used single-particle cryo–electron microscopy (cryo-EM) to obtain structures of the full complex in a lipid bilayer in the absence or presence of the inhibitor oligomycin at 3.6- and 3.8-angstrom resolution, respectively. To limit conformational heterogeneity, we locked the rotor in a single conformation by fusing the F6 subunit of the stator with the subunit of the rotor. Assembly of the enzyme with the F6- fusion caused a twisting of the rotor and a 9° rotation of ...
Source: ScienceNOW - May 10, 2018 Category: Science Authors: Srivastava, A. P., Luo, M., Zhou, W., Symersky, J., Bai, D., Chambers, M. G., Faraldo-Gomez, J. D., Liao, M., Mueller, D. M. Tags: Biochemistry, Online Only r-articles Source Type: news

Erratum for the Report "Translocation of a gut pathobiont drives autoimmunity in mice and humans" by S. Manfredo Vieira, M. Hiltensperger, V. Kumar, D. Zegarra-Ruiz, C. Dehner, N. Khan, F. R. C. Costa, E. Tiniakou, T. Greiling, W. Ruff, A. Barbieri, C. Kriegel, S. S. Mehta, J. R. Knight, D. Jain, A. L. Goodman, M. A. Kriegel
(Source: ScienceNOW)
Source: ScienceNOW - May 3, 2018 Category: Science Tags: Errata Source Type: news

First steps of translocation elucidated
(Source: ScienceNOW)
Source: ScienceNOW - April 19, 2018 Category: Science Authors: Hurtley, S. M. Tags: Molecular Biology twis Source Type: news

The nuclear translocation of the kinases p38 and JNK promotes inflammation-induced cancer
The stimulated nuclear translocation of signaling proteins, such as MAPKs, is a necessity for the initiation and regulation of their physiological functions. Previously, we determined that nuclear translocation of the MAPKs p38 and JNK involves binding to heterodimers comprising importin 3 and either importin 7 or importin 9. Here, we identified the importin-binding region in p38 and JNK and developed a myristoylated peptide targeting this site that we called PERY. The PERY peptide specifically blocked the interaction of p38 and JNK with the importins, restricted their nuclear translocation, and inhibited phosphorylation o...
Source: Signal Transduction Knowledge Environment - April 10, 2018 Category: Science Authors: Maik-Rachline, G., Zehorai, E., Hanoch, T., Blenis, J., Seger, R. Tags: STKE Research Articles Source Type: news

Translocation of a gut pathobiont drives autoimmunity in mice and humans
Despite multiple associations between the microbiota and immune diseases, their role in autoimmunity is poorly understood. We found that translocation of a gut pathobiont, Enterococcus gallinarum, to the liver and other systemic tissues triggers autoimmune responses in a genetic background predisposing to autoimmunity. Antibiotic treatment prevented mortality in this model, suppressed growth of E. gallinarum in tissues, and eliminated pathogenic autoantibodies and T cells. Hepatocyte–E. gallinarum cocultures induced autoimmune-promoting factors. Pathobiont translocation in monocolonized and autoimmune-prone mice indu...
Source: ScienceNOW - March 8, 2018 Category: Science Authors: Manfredo Vieira, S., Hiltensperger, M., Kumar, V., Zegarra-Ruiz, D., Dehner, C., Khan, N., Costa, F. R. C., Tiniakou, E., Greiling, T., Ruff, W., Barbieri, A., Kriegel, C., Mehta, S. S., Knight, J. R., Jain, D., Goodman, A. L., Kriegel, M. A. Tags: Immunology, Medicine, Diseases reports Source Type: news

Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation
The multidrug transporter permeability (P)–glycoprotein is an adenosine triphosphate (ATP)–binding cassette exporter responsible for clinical resistance to chemotherapy. P-glycoprotein extrudes toxic molecules and drugs from cells through ATP-powered conformational changes. Despite decades of effort, only the structures of the inward-facing conformation of P-glycoprotein are available. Here we present the structure of human P-glycoprotein in the outward-facing conformation, determined by cryo–electron microscopy at 3.4-angstrom resolution. The two nucleotide-binding domains form a closed dimer occluding t...
Source: ScienceNOW - February 22, 2018 Category: Science Authors: Kim, Y., Chen, J. Tags: Biochemistry, Medicine, Diseases reports Source Type: news