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  • Abl and Arg mediate cysteine cathepsin secretion to facilitate melanoma invasion and metastasis
    Sci. Signal. (IF 6.494) Pub Date : 2018-02-20
    Rakshamani Tripathi, Leann S. Fiore, Dana L. Richards, Yuchen Yang, Jinpeng Liu, Chi Wang, Rina Plattner

    The incidence of melanoma is increasing, particularly in young women, and the disease remains incurable for many because of its aggressive, metastatic nature and its high rate of resistance to conventional, targeted, and immunological agents. Cathepsins are proteases that are critical for melanoma progression and therapeutic resistance. Intracellular cathepsins cleave or degrade proteins that restrict cancer progression, whereas extracellular cathepsins directly cleave the extracellular matrix and activate proinvasive proteases in the tumor microenvironment. Cathepsin secretion is markedly increased in cancer cells. We investigated the signaling pathways leading to increased cathepsin secretion in melanoma cells. We found that the nonreceptor tyrosine kinases Abl and Arg (Abl/Arg) promoted the secretion of cathepsin B and cathepsin L by activating transcription factors (namely, Ets1, Sp1, and NF-κB/p65) that have key roles in the epithelial-mesenchymal transition (EMT), invasion, and therapeutic resistance. In some melanoma cell lines, Abl/Arg promoted the Ets1/p65-induced secretion of cathepsin B and cathepsin L in a kinase-independent manner, whereas in other melanoma lines, Abl/Arg promoted the kinase-dependent, Sp1/Ets1/p65–mediated induction of cathepsin L secretion and the Sp1/p65-mediated induction of cathepsin B secretion. As an indication of clinical relevance, the abundance of mRNAs encoding Abl/Arg, Sp1, Ets1, and cathepsins was positively correlated in primary melanomas, and Abl/Arg-driven invasion in culture and metastasis in vivo required cathepsin secretion. These data suggest that drugs targeting Abl kinases, many of which are FDA-approved, might inhibit cathepsin secretion in some melanomas and potentially other aggressive cancers harboring activated Abl kinases.

    更新日期:2018-02-21
  • The intracellular pyrimidine 5′-nucleotidase NT5C3A is a negative epigenetic factor in interferon and cytokine signaling
    Sci. Signal. (IF 6.494) Pub Date : 2018-02-20
    Latifa Al-Haj, Khalid S. A. Khabar

    The enzyme pyrimidine 5′-nucleotidase (NT5C3A), which mediates nucleotide catabolism, was previously thought to be restricted to blood cells. We showed that expression of the gene encoding NT5C3A was induced by type I interferons (IFNs) in multiple cell types and that NT5C3A suppressed cytokine production through inhibition of the nuclear factor κB (NF-κB) pathway. NT5C3A expression required both an intronic IFN-stimulated response element and the IFN-stimulated transcription factor IRF1. Overexpression of NT5C3A, but not of its catalytic mutants, suppressed IL-8 production by HEK293 cells. Whereas knockdown of NT5C3A enhanced tumor necrosis factor (TNF)–stimulated IL-8 production, it reduced the IFN-mediated suppression of Il8 expression. Overexpression of NT5C3A increased the abundance of NAD+ and the activation of the sirtuins SIRT1 and SIRT6, which are NAD+-dependent deacetylases. NT5C3A-stimulated sirtuin activity resulted in deacetylation of histone H3 and the NF-κB subunit RelA (also known as p65), both of which were associated with the proximal region of the Il8 promoter, thus repressing the transcription of Il8. Together, these data identify an anti-inflammatory pathway that depends on the catalytic activity of NT5C3A and functions as a negative feedback regulator of inflammatory cytokine signaling.

    更新日期:2018-02-21
  • Condemned by metabolism
    Sci. Signal. (IF 6.494) Pub Date : 2018-02-20
    Wei Wong

    The kinase RIP3 increases aerobic flux to produce reactive oxygen species, which enhances necrosome formation and necroptosis.

    更新日期:2018-02-21
  • A calcium-sensing receptor mutation causing hypocalcemia disrupts a transmembrane salt bridge to activate β-arrestin–biased signaling
    Sci. Signal. (IF 6.494) Pub Date : 2018-02-20
    Caroline M. Gorvin, Valerie N. Babinsky, Tomas Malinauskas, Peter H. Nissen, Anders J. Schou, Aylin C. Hanyaloglu, Christian Siebold, E. Yvonne Jones, Fadil M. Hannan, Rajesh V. Thakker

    The calcium-sensing receptor (CaSR) is a G protein–coupled receptor (GPCR) that signals through Gq/11 and Gi/o to stimulate cytosolic calcium (Ca2+i) and mitogen-activated protein kinase (MAPK) signaling to control extracellular calcium homeostasis. Studies of loss- and gain-of-function CASR mutations, which cause familial hypocalciuric hypercalcemia type 1 (FHH1) and autosomal dominant hypocalcemia type 1 (ADH1), respectively, have revealed that the CaSR signals in a biased manner. Thus, some mutations associated with FHH1 lead to signaling predominantly through the MAPK pathway, whereas mutations associated with ADH1 preferentially enhance Ca2+i responses. We report a previously unidentified ADH1-associated R680G CaSR mutation, which led to the identification of a CaSR structural motif that mediates biased signaling. Expressing CaSRR680G in HEK 293 cells showed that this mutation increased MAPK signaling without altering Ca2+i responses. Moreover, this gain of function in MAPK activity occurred independently of Gq/11 and Gi/o and was mediated instead by a noncanonical pathway involving β-arrestin proteins. Homology modeling and mutagenesis studies showed that the R680G CaSR mutation selectively enhanced β-arrestin signaling by disrupting a salt bridge formed between Arg680 and Glu767, which are located in CaSR transmembrane domain 3 and extracellular loop 2, respectively. Thus, our results demonstrate CaSR signaling through β-arrestin and the importance of the Arg680-Glu767 salt bridge in mediating signaling bias.

    更新日期:2018-02-21
  • Coordinating the overall stomatal response of plants: Rapid leaf-to-leaf communication during light stress
    Sci. Signal. (IF 6.494) Pub Date : 2018-02-20
    Amith R. Devireddy, Sara I. Zandalinas, Aurelio Gómez-Cadenas, Eduardo Blumwald, Ron Mittler

    The plant canopy functions as an aerial array of light-harvesting antennas. To achieve maximal yield, each leaf within this array and the array as a whole need to rapidly adjust to naturally occurring fluctuations in light intensity and quality. Excessive light stress triggers the closing of pores in leaves called stomata to minimize moisture loss. We found that different leaves within the canopy of an Arabidopsis thaliana plant, including leaves not directly exposed to light, coordinated stomatal closure in response to light stress by sending and receiving rapid systemic signals. This response required the plant hormones abscisic acid and jasmonic acid and was mediated by a rapid autopropagating wave of reactive oxygen species (ROS) production. Furthermore, this response depended on the function of genes encoding the ROS-generating NADPH oxidase RBOHD and various stomatal regulators, such as the anion channel SLAC1, GHR1 (guard cell hydrogen peroxide resistant 1), and lipoxygenase 1 (LOX1). Our findings reveal that plants function as highly dynamic and coordinated organisms, optimizing the overall response of their canopies to fluctuating light intensities.

    更新日期:2018-02-21
  • (A)GO for gene expression
    Sci. Signal. (IF 6.494) Pub Date : 2018-02-13
    Leslie K. Ferrarelli

    AGO1 promotes, rather than represses, gene expression in response to hormones and stress signaling in plants by binding chromatin.

    更新日期:2018-02-14
  • The unfolded protein response regulator ATF6 promotes mesodermal differentiation
    Sci. Signal. (IF 6.494) Pub Date : 2018-02-13
    Heike Kroeger, Neil Grimsey, Ryan Paxman, Wei-Chieh Chiang, Lars Plate, Ying Jones, Peter X. Shaw, JoAnn Trejo, Stephen H. Tsang, Evan Powers, Jeffery W. Kelly, R. Luke Wiseman, Jonathan H. Lin

    ATF6 encodes a transcription factor that is anchored in the endoplasmic reticulum (ER) and activated during the unfolded protein response (UPR) to protect cells from ER stress. Deletion of the isoform activating transcription factor 6α (ATF6α) and its paralog ATF6β results in embryonic lethality and notochord dysgenesis in nonhuman vertebrates, and loss-of-function mutations in ATF6α are associated with malformed neuroretina and congenital vision loss in humans. These phenotypes implicate an essential role for ATF6 during vertebrate development. We investigated this hypothesis using human stem cells undergoing differentiation into multipotent germ layers, nascent tissues, and organs. We artificially activated ATF6 in stem cells with a small-molecule ATF6 agonist and, conversely, inhibited ATF6 using induced pluripotent stem cells from patients with ATF6 mutations. We found that ATF6 suppressed pluripotency, enhanced differentiation, and unexpectedly directed mesodermal cell fate. Our findings reveal a role for ATF6 during differentiation and identify a new strategy to generate mesodermal tissues through the modulation of the ATF6 arm of the UPR.

    更新日期:2018-02-14
  • Educated natural killer cells show dynamic movement of the activating receptor NKp46 and confinement of the inhibitory receptor Ly49A
    Sci. Signal. (IF 6.494) Pub Date : 2018-02-13
    Elina Staaf, Per Niklas Hedde, Sunitha Bagawath Singh, Joachim Piguet, Enrico Gratton, Sofia Johansson

    Educated natural killer (NK) cells have inhibitory receptors specific for self major histocompatibility complex (MHC) class I molecules and kill cancer cells more efficiently than do NK cells that do not have such receptors (hyporesponsive NK cells). The mechanism behind this functional empowerment through education has so far not been fully described. In addition, distinctive phenotypic markers of educated NK cells at the single-cell level are lacking. We developed a refined version of the image mean square displacement (iMSD) method (called iMSD carpet analysis) and used it in combination with single-particle tracking to characterize the dynamics of the activating receptor NKp46 and the inhibitory receptor Ly49A on resting educated versus hyporesponsive murine NK cells. Most of the NKp46 and Ly49A molecules were restricted to microdomains; however, individual NKp46 molecules resided in these domains for shorter periods and diffused faster on the surface of educated, compared to hyporesponsive, NK cells. In contrast, the movement of Ly49A was more constrained in educated NK cells compared to hyporesponsive NK cells. Either disrupting the actin cytoskeleton or adding cholesterol to the cells prohibited activating signaling, suggesting that the dynamics of receptor movements within the cell membrane are critical for the proper activation of NK cells. The faster and more dynamic movement of NKp46 in educated NK cells may facilitate a swifter response to interactions with target cells.

    更新日期:2018-02-14
  • Structural basis for the interaction between the cell polarity proteins Par3 and Par6
    Sci. Signal. (IF 6.494) Pub Date : 2018-02-13
    Fabian A. Renschler, Susanne R. Bruekner, Paulin L. Salomon, Amrita Mukherjee, Lars Kullmann, Mira C. Schütz-Stoffregen, Christine Henzler, Tony Pawson, Michael P. Krahn, Silke Wiesner

    Polarity is a fundamental property of most cell types. The Par protein complex is a major driving force in generating asymmetrically localized protein networks and consists of atypical protein kinase C (aPKC), Par3, and Par6. Dysfunction of this complex causes developmental abnormalities and diseases such as cancer. We identified a PDZ domain–binding motif in Par6 that was essential for its interaction with Par3 in vitro and for Par3-mediated membrane localization of Par6 in cultured cells. In fly embryos, we observed that the PDZ domain–binding motif was functionally redundant with the PDZ domain in targeting Par6 to the cortex of epithelial cells. Our structural analyses by x-ray crystallography and NMR spectroscopy showed that both the PDZ1 and PDZ3 domains but not the PDZ2 domain in Par3 engaged in a canonical interaction with the PDZ domain–binding motif in Par6. Par3 thus has the potential to recruit two Par6 proteins simultaneously, which may facilitate the assembly of polarity protein networks through multivalent PDZ domain interactions.

    更新日期:2018-02-14
  • ER-phagy to alleviate stress
    Sci. Signal. (IF 6.494) Pub Date : 2018-02-06
    Annalisa M. VanHook

    Selective autophagy of the endoplasmic reticulum protects the secretory cells of the pancreas.

    更新日期:2018-02-08
  • The CCR4-NOT deadenylase complex controls Atg7-dependent cell death and heart function
    Sci. Signal. (IF 6.494) Pub Date : 2018-02-06
    Tomokazu Yamaguchi, Takashi Suzuki, Teruki Sato, Akinori Takahashi, Hiroyuki Watanabe, Ayumi Kadowaki, Miyuki Natsui, Hideaki Inagaki, Satoko Arakawa, Shinji Nakaoka, Yukio Koizumi, Shinsuke Seki, Shungo Adachi, Akira Fukao, Toshinobu Fujiwara, Tohru Natsume, Akinori Kimura, Masaaki Komatsu, Shigeomi Shimizu, Hiroshi Ito, Yutaka Suzuki, Josef M. Penninger, Tadashi Yamamoto, Yumiko Imai, Keiji Kuba

    Shortening and removal of the polyadenylate [poly(A)] tail of mRNA, a process called deadenylation, is a key step in mRNA decay that is mediated through the CCR4-NOT (carbon catabolite repression 4–negative on TATA-less) complex. In our investigation of the regulation of mRNA deadenylation in the heart, we found that this complex was required to prevent cell death. Conditional deletion of the CCR4-NOT complex components Cnot1 or Cnot3 resulted in the formation of autophagic vacuoles and cardiomyocyte death, leading to lethal heart failure accompanied by long QT intervals. Cnot3 bound to and shortened the poly(A) tail of the mRNA encoding the key autophagy regulator Atg7. In Cnot3-depleted hearts, Atg7 expression was posttranscriptionally increased. Genetic ablation of Atg7, but not Atg5, increased survival and partially restored cardiac function of Cnot1 or Cnot3 knockout mice. We further showed that in Cnot3-depleted hearts, Atg7 interacted with p53 and modulated p53 activity to induce the expression of genes encoding cell death–promoting factors in cardiomyocytes, indicating that defects in deadenylation in the heart aberrantly activated Atg7 and p53 to promote cell death. Thus, mRNA deadenylation mediated by the CCR4-NOT complex is crucial to prevent Atg7-induced cell death and heart failure, suggesting a role for mRNA deadenylation in targeting autophagy genes to maintain normal cardiac homeostasis.

    更新日期:2018-02-08
  • G protein–coupled receptors control the sensitivity of cells to the morphogen Sonic Hedgehog
    Sci. Signal. (IF 6.494) Pub Date : 2018-02-06
    Ganesh V. Pusapati, Jennifer H. Kong, Bhaven B. Patel, Mina Gouti, Andreas Sagner, Ria Sircar, Giovanni Luchetti, Philip W. Ingham, James Briscoe, Rajat Rohatgi

    The morphogen Sonic Hedgehog (SHH) patterns tissues during development by directing cell fates in a concentration-dependent manner. The SHH signal is transmitted across the membrane of target cells by the heptahelical transmembrane protein Smoothened (SMO), which activates the GLI family of transcription factors through a mechanism that is undefined in vertebrates. Using CRISPR-edited null alleles and small-molecule inhibitors, we systematically analyzed the epistatic interactions between SMO and three proteins implicated in SMO signaling: the heterotrimeric G protein subunit GαS, the G protein–coupled receptor kinase 2 (GRK2), and the GαS-coupled receptor GPR161. Our experiments uncovered a signaling mechanism that modifies the sensitivity of target cells to SHH and consequently changes the shape of the SHH dose-response curve. In both fibroblasts and spinal neural progenitors, the loss of GPR161, previously implicated as an inhibitor of basal SHH signaling, increased the sensitivity of target cells across the entire spectrum of SHH concentrations. Even in cells lacking GPR161, GRK2 was required for SHH signaling, and Gαs, which promotes the activation of protein Kinase A (PKA), antagonized SHH signaling. We propose that the sensitivity of target cells to Hedgehog morphogens, and the consequent effects on gene expression and differentiation outcomes, can be controlled by signals from G protein–coupled receptors that converge on Gαs and PKA.

    更新日期:2018-02-08
  • Unraveling the CNOT: A new player in the autophagy–cell death nexus
    Sci. Signal. (IF 6.494) Pub Date : 2018-02-06
    Saumya Das

    Autophagy plays a context-dependent role in cardiac homeostasis. In this issue of Science Signaling, Yamaguchi et al. delineate a role for CCR4-NOT–mediated mRNA deadenylation in preventing the autophagy factor Atg7 from coactivating p53-mediated transcription of cell death genes in the heart.

    更新日期:2018-02-08
  • Grking the Smoothened signal
    Sci. Signal. (IF 6.494) Pub Date : 2018-02-06
    Hayley J. Sharpe, Frederic J. de Sauvage

    The kinase GRK2 has been linked to the clinically important Hedgehog (HH) signaling pathway, where it is paradoxically required for signal transduction yet also promotes internalization and degradation of the critical HH signal transducer Smoothened. Two reports by Li et al. and Pusapati et al. in this issue of Science Signaling provide new insights into the role of GRK2 in HH signaling.

    更新日期:2018-02-08
  • Hedgehog reciprocally controls trafficking of Smo and Ptc through the Smurf family of E3 ubiquitin ligases
    Sci. Signal. (IF 6.494) Pub Date : 2018-02-06
    Shuang Li, Shuangxi Li, Bing Wang, Jin Jiang

    Hedgehog (Hh) induces signaling by promoting the reciprocal trafficking of its receptor Patched (Ptc) and the signal transducer Smoothened (Smo), which is inhibited by Ptc, at the cell surface. We identified Smurf family E3 ubiquitin ligases as essential for Smo ubiquitylation and cell surface clearance and demonstrated that Smurf family members mediate the reciprocal trafficking of Ptc and Smo in Drosophila melanogaster. G protein–coupled receptor kinase 2 (Gprk2)–mediated phosphorylation of Smurf promoted Smo ubiquitylation by increasing the recruitment of Smurf to Smo, whereas protein kinase A (PKA)–mediated phosphorylation of Smo caused Smurf to dissociate from Smo, thereby inhibiting Smo ubiquitylation. Smo and Ptc competed for the same pool of Smurf family E3 ubiquitin ligases, and Hh promoted Ptc ubiquitylation and degradation by disrupting the association of Smurf family E3 ubiquitin ligases with Smo and stimulating their binding to Ptc. Our study identifies the E3 ubiquitin ligases that target Smo and provides insight into how Hh regulates the reciprocal trafficking of its receptor and signal transducer.

    更新日期:2018-02-08
  • SILAC identifies LAD1 as a filamin-binding regulator of actin dynamics in response to EGF and a marker of aggressive breast tumors
    Sci. Signal. (IF 6.494) Pub Date : 2018-01-30
    Lee Roth, Swati Srivastava, Moshit Lindzen, Aldema Sas-Chen, Michal Sheffer, Mattia Lauriola, Yehoshua Enuka, Ashish Noronha, Maicol Mancini, Sara Lavi, Gabi Tarcic, Gur Pines, Nava Nevo, Ori Heyman, Tamar Ziv, Oscar M. Rueda, Davide Gnocchi, Eli Pikarski, Arie Admon, Carlos Caldas, Yosef Yarden

    Mutations mimicking growth factor–induced proliferation and motility characterize aggressive subtypes of mammary tumors. To unravel currently unknown players in these processes, we performed phosphoproteomic analysis on untransformed mammary epithelial cells (MCF10A) that were stimulated in culture with epidermal growth factor (EGF). We identified ladinin-1 (LAD1), a largely uncharacterized protein to date, as a phosphorylation-regulated mediator of the EGF-to-ERK pathway. Further experiments revealed that LAD1 mediated the proliferation and migration of mammary cells. LAD1 was transcriptionally induced, phosphorylated, and partly colocalized with actin stress fibers in response to EGF. Yeast two-hybrid, proximity ligation, and coimmunoprecipitation assays revealed that LAD1 bound to actin–cross-linking proteins called filamins. Cosedimentation analyses indicated that LAD1 played a role in actin dynamics, probably in collaboration with the scaffold protein 14-3-3σ (also called SFN). Depletion of LAD1 decreased the expression of transcripts associated with cell survival and inhibited the growth of mammary xenografts in an animal model. Furthermore, LAD1 predicts poor patient prognosis and is highly expressed in aggressive subtypes of breast cancer characterized as integrative clusters 5 and 10, which partly correspond to triple-negative and HER2-positive tumors. Thus, these findings reveal a cytoskeletal component that is critically involved in cell migration and the acquisition of oncogenic attributes in human mammary tumors.

    更新日期:2018-01-31
  • KIF22 coordinates CAR and EGFR dynamics to promote cancer cell proliferation
    Sci. Signal. (IF 6.494) Pub Date : 2018-01-30
    Rosemary Pike, Elena Ortiz-Zapater, Brooke Lumicisi, George Santis, Maddy Parsons

    The coxsackievirus and adenovirus receptor (CAR) is a transmembrane receptor that plays a key role in cell-cell adhesion. CAR is found in normal epithelial cells and is increased in abundance in various human tumors, including lung carcinomas. We investigated the potential mechanisms by which CAR contributes to cancer cell growth and found that depletion of CAR in human lung cancer cells reduced anchorage-independent growth, epidermal growth factor (EGF)–dependent proliferation, and tumor growth in vivo. EGF induced the phosphorylation of CAR and its subsequent relocalization to cell junctions through the activation of the kinase PKCδ. EGF promoted the binding of CAR to the chromokinesin KIF22. KIF22-dependent regulation of microtubule dynamics led to delayed EGFR internalization, enhanced EGFR signaling, and coordination of CAR dynamics at cell-cell junctions. These data suggest a role for KIF22 in the coordination of membrane receptors and provide potential new therapeutic strategies to combat lung tumor growth.

    更新日期:2018-01-31
  • Sensing bacterial infection
    Sci. Signal. (IF 6.494) Pub Date : 2018-01-30
    John F. Foley

    The endoplasmic reticulum–resident adaptor protein ERAdP senses bacterial c-di-AMP to stimulate an immune response.

    更新日期:2018-01-31
  • Fluorescent Ca2+ indicators directly inhibit the Na,K-ATPase and disrupt cellular functions
    Sci. Signal. (IF 6.494) Pub Date : 2018-01-30
    Nathan A. Smith, Benjamin T. Kress, Yuan Lu, Devin Chandler-Militello, Abdellatif Benraiss, Maiken Nedergaard

    Fluorescent Ca2+ indicators have been essential for the analysis of Ca2+ signaling events in various cell types. We showed that chemical Ca2+ indicators, but not a genetically encoded Ca2+ indicator, potently suppressed the activity of Na+- and K+-dependent adenosine triphosphatase (Na,K-ATPase), independently of their Ca2+ chelating activity. Loading of commonly used Ca2+ indicators, including Fluo-4 acetoxymethyl (AM), Rhod-2 AM, and Fura-2 AM, and of the Ca2+ chelator BAPTA AM into cultured mouse or human neurons, astrocytes, cardiomyocytes, or kidney proximal tubule epithelial cells suppressed Na,K-ATPase activity by 30 to 80%. Ca2+ indicators also suppressed the agonist-induced activation of the Na,K-ATPase, altered metabolic status, and caused a dose-dependent loss of cell viability. Loading of Ca2+ indicators into mice, which is carried out for two-photon imaging, markedly altered brain extracellular concentrations of K+ and ATP. These results suggest that a critical review of data obtained with chemical Ca2+ indicators may be necessary.

    更新日期:2018-01-31
  • EGFR-induced cytoskeletal changes drive complex cell behaviors: The tip of the iceberg
    Sci. Signal. (IF 6.494) Pub Date : 2018-01-30
    Christine Chiasson-MacKenzie, Andrea I. McClatchey

    Cytoskeletal networks are dramatically reorganized upon EGF stimulation to enable complex cell behaviors such as cell-cell communication, migration and invasion, and cell division. In this issue of Science Signaling, Roth et al. and Pike et al. use proteomic methods to identify several effectors of EGF responses. The findings show the interdependent nature of growth factor signaling and the cytoskeleton and identify potential new therapeutic targets for treating cancer and other growth factor–driven diseases.

    更新日期:2018-01-31
  • Intron splicing for lipid biosynthesis
    Sci. Signal. (IF 6.494) Pub Date : 2018-01-23
    Wei Wong

    mTORC1 regulates de novo lipogenesis by enhancing the splicing of introns from transcripts encoding lipogenic enzymes.

    更新日期:2018-01-24
  • Biased signaling by thyroid-stimulating hormone receptor–specific antibodies determines thyrocyte survival in autoimmunity
    Sci. Signal. (IF 6.494) Pub Date : 2018-01-23
    Syed A. Morshed, Risheng Ma, Rauf Latif, Terry F. Davies

    The thyroid-stimulating hormone receptor (TSHR) is a heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptor (GPCR). Autoimmune hyperthyroidism, commonly known as Graves’ disease (GD), is caused by stimulating autoantibodies to the TSHR. We previously described TSHR-specific antibodies (TSHR-Abs) in GD that recognize linear epitopes in the cleavage region of the TSHR ectodomain (C-TSHR-Abs) and induce thyroid cell apoptosis instead of stimulating the TSHR. We found that C-TSHR-Abs entered the cell through clathrin-mediated endocytosis but did not trigger endosomal maturation and failed to undergo normal vesicular sorting and trafficking. We found that stimulating TSHR-Abs (S-TSHR-Abs) activated Gαs and, to a lesser extent, Gαq but that C-TSHR-Abs failed to activate any of the G proteins normally activated in response to TSH. Furthermore, specific inhibition of G proteins in the presence of S-TSHR-mAbs or TSH resulted in a similar failure of endosomal maturation as that caused by C-TSHR-mAbs. Hence, whereas S-TSHR-mAbs and TSH contributed to normal vesicular trafficking of TSHR through the activation of major G proteins, the C-TSHR-Abs resulted in GRK2- and β-arrestin-1–dependent biased signaling, which is interpreted as a danger signal by the cell. Our observations suggest that the binding of antibodies to different TSHR epitopes may decrease cell survival. Antibody-induced cell injury and the response to cell death amplify the loss of self-tolerance, which most likely helps to perpetuate GPCR-mediated autoimmunity.

    更新日期:2018-01-24
  • Guanabenz inhibits TLR9 signaling through a pathway that is independent of eIF2α dephosphorylation by the GADD34/PP1c complex
    Sci. Signal. (IF 6.494) Pub Date : 2018-01-23
    Jessica Perego, Andreia Mendes, Clarisse Bourbon, Voahirana Camosseto, Alexis Combes, Hong Liu, Thien-Phong Vu Manh, Alexandre Dalet, Lionel Chasson, Lionel Spinelli, Nathalie Bardin, Laurent Chiche, Manuel A. S. Santos, Evelina Gatti, Philippe Pierre

    Endoplasmic reticulum (ER) stress triggers or amplifies inflammatory signals and cytokine production in immune cells. Upon the resolution of ER stress, the inducible phosphatase 1 cofactor GADD34 promotes the dephosphorylation of the initiation factor eIF2α, thereby enabling protein translation to resume. Several aminoguanidine compounds, such as guanabenz, perturb the eIF2α phosphorylation-dephosphorylation cycle and protect different cell or tissue types from protein misfolding and degeneration. We investigated how pharmacological interference with the eIF2α pathway could be beneficial to treat autoinflammatory diseases dependent on proinflammatory cytokines and type I interferons (IFNs), the production of which is regulated by GADD34 in dendritic cells (DCs). In mouse and human DCs and B cells, guanabenz prevented the activation of Toll-like receptor 9 (TLR9) by CpG oligodeoxynucleotides or DNA-immunoglobulin complexes in endosomes. In vivo, guanabenz protected mice from CpG oligonucleotide–dependent cytokine shock and decreased autoimmune symptom severity in a chemically induced model of systemic lupus erythematosus. However, we found that guanabenz exerted its inhibitory effect independently of GADD34 activity on eIF2α and instead decreased the abundance of CH25H, a cholesterol hydroxylase linked to antiviral immunity. Our results therefore suggest that guanabenz and similar compounds could be used to treat type I IFN–dependent pathologies and that CH25H could be a therapeutic target to control these diseases.

    更新日期:2018-01-24
  • Intracellular cavity of sensor domain controls allosteric gating of TRPA1 channel
    Sci. Signal. (IF 6.494) Pub Date : 2018-01-23
    Lucie Zimova, Viktor Sinica, Anna Kadkova, Lenka Vyklicka, Vlastimil Zima, Ivan Barvik, Viktorie Vlachova

    Transient receptor potential ankyrin 1 (TRPA1) is a temperature-sensitive ion channel activated by various pungent and irritant compounds that can produce pain in humans. Its activation involves an allosteric mechanism whereby electrophilic agonists evoke interactions within cytosolic domains and open the channel pore through an integrated nexus formed by intracellular membrane proximal regions that are densely packed beneath the lower segment of the S1–S4 sensor domain. Studies indicate that this part of the channel may contain residues that form a water-accessible cavity that undergoes changes in solvation during channel gating. We identified conserved polar residues facing the putative lower crevice of the sensor domain that were crucial determinants of the electrophilic, voltage, and calcium sensitivity of the TRPA1 channel. This part of the sensor may also comprise a domain capable of binding to membrane phosphoinositides through which gating of the channel is regulated in a state-dependent manner.

    更新日期:2018-01-24
  • Learning-dependent chromatin remodeling highlights noncoding regulatory regions linked to autism
    Sci. Signal. (IF 6.494) Pub Date : 2018-01-16
    John N. Koberstein, Shane G. Poplawski, Mathieu E. Wimmer, Giulia Porcari, Charlly Kao, Bruce Gomes, Davide Risso, Hakon Hakonarson, Nancy R. Zhang, Robert T. Schultz, Ted Abel, Lucia Peixoto

    Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder that is associated with genetic risk factors. Most human disease-associated single-nucleotide polymorphisms (SNPs) are not located in genes but rather are in regulatory regions that control gene expression. The function of regulatory regions is determined through epigenetic mechanisms. Parallels between the cellular basis of development and the formation of long-term memory have long been recognized, particularly the role of epigenetic mechanisms in both processes. We analyzed how learning alters chromatin accessibility in the mouse hippocampus using a new high-throughput sequencing bioinformatics strategy we call DEScan (differential enrichment scan). DEScan, which enabled the analysis of data from epigenomic experiments containing multiple replicates, revealed changes in chromatin accessibility at 2365 regulatory regions—most of which were promoters. Learning-regulated promoters were active during forebrain development in mice and were enriched in epigenetic modifications indicative of bivalent promoters. These promoters were disproportionally intronic, showed a complex relationship with gene expression and alternative splicing during memory consolidation and retrieval, and were enriched in the data set relative to known ASD risk genes. Genotyping in a clinical cohort within one of these promoters (SHANK3 promoter 6) revealed that the SNP rs6010065 was associated with ASD. Our data support the idea that learning recapitulates development at the epigenetic level and demonstrate that behaviorally induced epigenetic changes in mice can highlight regulatory regions relevant to brain disorders in patients.

    更新日期:2018-01-17
  • Inactivating mutations in Drosha mediate vascular abnormalities similar to hereditary hemorrhagic telangiectasia
    Sci. Signal. (IF 6.494) Pub Date : 2018-01-16
    Xuan Jiang, Whitney L. Wooderchak-Donahue, Jamie McDonald, Prajakta Ghatpande, Mai Baalbaki, Melissa Sandoval, Daniel Hart, Hilary Clay, Shaun Coughlin, Giorgio Lagna, Pinar Bayrak-Toydemir, Akiko Hata

    The transforming growth factor–β (TGF-β) and bone morphogenetic protein (BMP) family of cytokines critically regulates vascular morphogenesis and homeostasis. Impairment of TGF-β or BMP signaling leads to heritable vascular disorders, including hereditary hemorrhagic telangiectasia (HHT). Drosha, a key enzyme for microRNA (miRNA) biogenesis, also regulates the TGF-β and BMP pathway through interaction with Smads and their joint control of gene expression through miRNAs. We report that mice lacking Drosha in the vascular endothelium developed a vascular phenotype resembling HHT that included dilated and disorganized vasculature, arteriovenous fistulae, and hemorrhages. Exome sequencing of HHT patients who lacked known pathogenic mutations revealed an overrepresentation of rare nonsynonymous variants of DROSHA. Two of these DROSHA variants (P100L and R279L) did not interact with Smads and were partially catalytically active. In zebrafish, expression of these mutants or morpholino-directed knockdown of Drosha resulted in angiogenesis defects and abnormal vascular permeability. Together, our studies point to an essential role of Drosha in vascular development and the maintenance of vascular integrity, and reveal a previously unappreciated link between Drosha dysfunction and HHT.

    更新日期:2018-01-17
  • Functional changes of AMPA responses in human induced pluripotent stem cell–derived neural progenitors in fragile X syndrome
    Sci. Signal. (IF 6.494) Pub Date : 2018-01-16
    Venkat Swaroop Achuta, Tommi Möykkynen, Ulla-Kaisa Peteri, Giorgio Turconi, Claudio Rivera, Kari Keinänen, Maija L. Castrén

    Altered neuronal network formation and function involving dysregulated excitatory and inhibitory circuits are associated with fragile X syndrome (FXS). We examined functional maturation of the excitatory transmission system in FXS by investigating the response of FXS patient–derived neural progenitor cells to the glutamate analog (AMPA). Neural progenitors derived from induced pluripotent stem cell (iPSC) lines generated from boys with FXS had augmented intracellular Ca2+ responses to AMPA and kainate that were mediated by Ca2+-permeable AMPA receptors (CP-AMPARs) lacking the GluA2 subunit. Together with the enhanced differentiation of glutamate-responsive cells, the proportion of CP-AMPAR and N-methyl-d-aspartate (NMDA) receptor–coexpressing cells was increased in human FXS progenitors. Differentiation of cells lacking GluA2 was also increased and paralleled the increased inward rectification in neural progenitors derived from Fmr1-knockout mice (the FXS mouse model). Human FXS progenitors had increased the expression of the precursor and mature forms of miR-181a, a microRNA that represses translation of the transcript encoding GluA2. Blocking GluA2-lacking, CP-AMPARs reduced the neurite length of human iPSC-derived control progenitors and further reduced the shortened length of neurites in human FXS progenitors, supporting the contribution of CP-AMPARs to the regulation of progenitor differentiation. Furthermore, we observed reduced expression of Gria2 (the GluA2-encoding gene) in the frontal lobe of FXS mice, consistent with functional changes of AMPARs in FXS. Increased Ca2+ influx through CP-AMPARs may increase the vulnerability and affect the differentiation and migration of distinct cell populations, which may interfere with normal circuit formation in FXS.

    更新日期:2018-01-17
  • New connections: Signaling in learning disability
    Sci. Signal. (IF 6.494) Pub Date : 2018-01-16
    Leslie K. Ferrarelli

    Research in this issue of Science Signaling and the Archives brings us steps closer to understanding the origins of learning disability.

    更新日期:2018-01-17
  • β-Arrestin–biased β-adrenergic signaling promotes extinction learning of cocaine reward memory
    Sci. Signal. (IF 6.494) Pub Date : 2018-01-09
    Bing Huang, Youxing Li, Deqin Cheng, Guanhong He, Xing Liu, Lan Ma

    Extinction learning of cocaine-associated contextual cues can help prevent cocaine addicts from relapsing. Pharmacological manipulation of β-adrenergic receptor (β-AR) during extinction learning is being developed as a potential strategy to treat drug addiction. We demonstrated that the extinction learning of cocaine-associated memory was mediated by β-arrestin2–biased but not heterotrimeric guanine nucleotide–binding protein (G protein)–dependent β-adrenergic signaling. We found that administration of the nonbiased β-AR antagonist propranolol, but not the G protein–biased β-AR antagonist carvedilol, blocked extinction learning of cocaine-conditioned place preference and the associated ERK activation in the infralimbic prefrontal cortex. Overexpression of β-arrestin2 in the infralimbic prefrontal cortex promoted extinction learning, which was blocked by propranolol. Knockout of β-arrestin2 in the infralimbic prefrontal cortex, specifically in excitatory neurons, impaired extinction learning of cocaine-conditioned place preference, which was not rescued by carvedilol. β-Arrestin2 signaling in infralimbic excitatory neurons was also required for the extinction learning in the cocaine self-administration model. Our results suggest that β-arrestin–biased β-adrenergic signaling in the infralimbic prefrontal cortex regulates extinction learning of cocaine-associated memories and could be therapeutically targeted to treat addiction.

    更新日期:2018-01-10
  • ATM directs DNA damage responses and proteostasis via genetically separable pathways
    Sci. Signal. (IF 6.494) Pub Date : 2018-01-09
    Ji-Hoon Lee, Michael R. Mand, Chung-Hsuan Kao, Yi Zhou, Seung W. Ryu, Alicia L. Richards, Joshua J. Coon, Tanya T. Paull

    The protein kinase ATM is a master regulator of the DNA damage response but also responds directly to oxidative stress. Loss of ATM causes ataxia telangiectasia, a neurodegenerative disorder with pleiotropic symptoms that include cerebellar dysfunction, cancer, diabetes, and premature aging. We genetically separated the activation of ATM by DNA damage from that by oxidative stress using separation-of-function mutations. We found that deficient activation of ATM by the Mre11-Rad50-Nbs1 complex and DNA double-strand breaks resulted in loss of cell viability, checkpoint activation, and DNA end resection in response to DNA damage. In contrast, loss of oxidative activation of ATM had minimal effects on DNA damage–related outcomes but blocked ATM-mediated initiation of checkpoint responses after oxidative stress and resulted in deficiencies in mitochondrial function and autophagy. In addition, expression of a variant ATM incapable of activation by oxidative stress resulted in widespread protein aggregation. These results indicate a direct relationship between the mechanism of ATM activation and its effects on cellular metabolism and DNA damage responses in human cells and implicate ATM in the control of protein homeostasis.

    更新日期:2018-01-10
  • Ca2+-dependent demethylation of phosphatase PP2Ac promotes glucose deprivation–induced cell death independently of inhibiting glycolysis
    Sci. Signal. (IF 6.494) Pub Date : 2018-01-09
    Ha Yin Lee, Yoko Itahana, Stefan Schuechner, Masahiro Fukuda, H. Shawn Je, Egon Ogris, David M. Virshup, Koji Itahana

    Cancer cells increase glucose metabolism to support aerobic glycolysis. However, only some cancer cells are acutely sensitive to glucose withdrawal, and the underlying mechanism of this selective sensitivity is unclear. We showed that glucose deprivation initiates a cell death pathway in cancer cells that is dependent on the kinase RIPK1. Glucose withdrawal triggered rapid plasma membrane depolarization and an influx of extracellular calcium into the cell through the L-type calcium channel Cav1.3 (CACNA1D), followed by activation of the kinase CAMK1. CAMK1 and the demethylase PPME1 were required for the subsequent demethylation and inactivation of the catalytic subunit of the phosphatase PP2A (PP2Ac) and the phosphorylation of RIPK1. Plasma membrane depolarization, PP2Ac demethylation, and cell death were prevented by glucose and, unexpectedly, by its nonmetabolizable analog 2-deoxy-d-glucose (2-DG), a glycolytic inhibitor. These findings reveal a previously unknown function of glucose as a signaling molecule that protects cells from death induced by plasma membrane depolarization, independently of its role in glycolysis. Components of this cancer cell death pathway represent potential therapeutic targets against cancer.

    更新日期:2018-01-10
  • Antibiotics directly affect host cell metabolism
    Sci. Signal. (IF 6.494) Pub Date : 2018-01-09
    Annalisa M. VanHook

    Antibiotic treatment alters host cell metabolism in a manner that affects both the efficacy of the drug and the immune response to infection.

    更新日期:2018-01-10
  • The endoplasmic reticulum–residing chaperone BiP is short-lived and metabolized through N-terminal arginylation
    Sci. Signal. (IF 6.494) Pub Date : 2018-01-02
    Sang Mi Shim, Ha Rim Choi, Ki Woon Sung, Yoon Jee Lee, Sung Tae Kim, Daeho Kim, Su Ran Mun, Joonsung Hwang, Hyunjoo Cha-Molstad, Aaron Ciechanover, Bo Yeon Kim, Yong Tae Kwon

    BiP and other endoplasmic reticulum (ER)–resident proteins are thought to be metabolically stable and to function primarily in the ER lumen. We sought to assess how the abundance of these proteins dynamically fluctuates in response to various stresses and how their subpopulations are relocated to non-ER compartments such as the cytosol. We showed that the molecular chaperone BiP (also known as GRP78) was short-lived under basal conditions and ER stress. The turnover of BiP was in part driven by its amino-terminal arginylation (Nt-arginylation) by the arginyltransferase ATE1, which generated an autophagic N-degron of the N-end rule pathway. ER stress elicited the formation of R-BiP, an effect that was increased when the proteasome was also inhibited. Nt-arginylation correlated with the cytosolic relocalization of BiP under the types of stress tested. The cytosolic relocalization of BiP did not require the functionality of the unfolded protein response or the Sec61- or Derlin1-containing translocon. A key inhibitor of the turnover and Nt-arginylation of BiP was HERP (homocysteine-responsive ER protein), a 43-kDa ER membrane–integrated protein that is an essential component of ER-associated protein degradation. Pharmacological inhibition of the ER-Golgi secretory pathway also suppressed R-BiP formation. Finally, we showed that cytosolic R-BiP induced by ER stress and proteasomal inhibition was routed to autophagic vacuoles and possibly additional metabolic fates. These results suggest that Nt-arginylation is a posttranslational modification that modulates the function, localization, and metabolic fate of ER-resident proteins.

    更新日期:2018-01-03
  • Blockade of TNFR2 signaling enhances the immunotherapeutic effect of CpG ODN in a mouse model of colon cancer
    Sci. Signal. (IF 6.494) Pub Date : 2018-01-02
    Yingjie Nie, Jiang He, Hidekazu Shirota, Anna L. Trivett, De Yang, Dennis M. Klinman, Joost J. Oppenheim, Xin Chen

    Through the tumor necrosis factor (TNF) receptor type II (TNFR2), TNF preferentially activates, expands, and promotes the phenotypic stability of CD4+Foxp3+regulatory T (Treg) cells. Those Tregcells that have a high abundance of TNFR2 have the maximal immunosuppressive capacity. We investigated whether targeting TNFR2 could effectively suppress the activity of Tregcells and consequently enhance the efficacy of cancer immunotherapy. We found that, relative to a suboptimal dose of the immunostimulatory Toll-like receptor 9 ligand CpG oligodeoxynucleotide (ODN), the combination of the suboptimal dose of CpG ODN with the TNFR2-blocking antibody M861 more markedly inhibited the growth of subcutaneously grafted mouse CT26 colon tumor cells. This resulted in markedly fewer TNFR2+Tregcells and more interferon-γ–positive (IFN-γ+) CD8+cytotoxic T lymphocytes infiltrating the tumor and improved long-term tumor-free survival in the mouse cohort. Tumor-free mice were resistant to rechallenge by the same but not unrelated (4T1 breast cancer) cells. Treatment with the combination of TNFR2-blocking antibody and a CD25-targeted antibody also resulted in enhanced inhibition of tumor growth in a syngeneic 4T1 mouse model of breast cancer. Thus, the combination of a TNFR2 inhibitor and an immunotherapeutic stimulant may represent a more effective treatment strategy for various cancers.

    更新日期:2018-01-03
  • Structural principles of tumor necrosis factor superfamily signaling
    Sci. Signal. (IF 6.494) Pub Date : 2018-01-02
    Éva S. Vanamee, Denise L. Faustman

    The tumor necrosis factor (TNF) ligand and receptor superfamilies play an important role in cell proliferation, survival, and death. Stimulating or inhibiting TNF superfamily signaling pathways is expected to have therapeutic benefit for patients with various diseases, including cancer, autoimmunity, and infectious diseases. We review our current understanding of the structure and geometry of TNF superfamily ligands, receptors, and their interactions. A trimeric ligand and three receptors, each binding at the interface of two ligand monomers, form the basic unit of signaling. Clustering of multiple receptor subunits is necessary for efficient signaling. Current reports suggest that the receptors are prearranged on the cell surface in a “nonsignaling,” resting state in a large hexagonal structure of antiparallel dimers. Receptor activation requires ligand binding, and cross-linking antibodies can stabilize the receptors, thereby maintaining the active, signaling state. On the other hand, an antagonist antibody that locks receptor arrangement in antiparallel dimers effectively blocks signaling. This model may aid the design of more effective TNF signaling–targeted therapies.

    更新日期:2018-01-03
  • Predicting the future of signaling for 2018
    Sci. Signal. (IF 6.494) Pub Date : 2018-01-02
    Michael B. Yaffe

    In this Editorial, the Chief Scientific Editor ofScience Signalingpredicts some of the emerging areas to watch for advances in signaling research in 2018.

    更新日期:2018-01-03
  • New connections: Stimulating immune memory against cancer
    Sci. Signal. (IF 6.494) Pub Date : 2018-01-02
    Leslie K. Ferrarelli

    Future immunotherapies may stimulate immune system attack as well as memory against cancer to prevent relapse in patients.

    更新日期:2018-01-03
  • The depalmitoylase APT1 directs the asymmetric partitioning of Notch and Wnt signaling during cell division
    Sci. Signal. (IF 6.494) Pub Date : 2018-01-02
    Ewa Stypulkowski, Irfan A. Asangani, Eric S. Witze

    Asymmetric cell division results in two distinctly fated daughter cells. A molecular hallmark of asymmetric division is the unequal partitioning of cell fate determinants. We have previously established that growth factor signaling promotes protein depalmitoylation to foster polarized protein localization, which, in turn, drives migration and metastasis. We report protein palmitoylation as a key mechanism for the asymmetric partitioning of the cell fate determinants Numb and β-catenin through the activity of the depalmitoylating enzyme APT1. Using point mutations, we showed that specific palmitoylated residues on Numb were required for its asymmetric localization. By live-cell imaging, we showed that reciprocal interactions between APT1 and the Rho family GTPase CDC42 promoted the asymmetric localization of Numb and β-catenin to the plasma membrane. This, in turn, restricted Notch- or Wnt-responsive transcriptional activity to one daughter cell. Moreover, we showed that altering APT1 abundance changed the transcriptional signatures of MDA-MB-231 triple receptor–negative breast cancer cells, similar to changes in Notch and β-catenin–mediated Wnt signaling. We also showed that loss of APT1 depleted a specific subpopulation of tumorigenic cells in colony formation assays. Together, our findings suggest that APT1-mediated depalmitoylation is a major mechanism of asymmetric cell division that maintains Notch- and Wnt-associated protein dynamics, gene expression, and cellular functions.

    更新日期:2018-01-03
  • IL-2Rβ abundance differentially tunes IL-2 signaling dynamics in CD4+ and CD8+ T cells
    Sci. Signal. (IF 6.494) Pub Date : 2017-12-19
    Geoffrey A. Smith, Jack Taunton, Arthur Weiss

    Interleukin-2 (IL-2) stimulates both activated CD4+and CD8+T cells to proliferate. IL-2 signals through an identical receptor complex and promotes the same dose-dependent phosphorylation of the canonical transcription factor STAT5 in both cell types. Despite this, CD8+T cells enter the S phase earlier and proliferate to a greater extent than do CD4+T cells in response to IL-2. We identified distinct IL-2 signaling dynamics in CD4+and CD8+T cells. In IL-2–stimulated CD8+T cells, STAT5 phosphorylation increased rapidly and was sustained for 6 hours. In contrast, CD4+T cells had a biphasic response, with maxima at 15 min and 2 to 4 hours after stimulation. Both cell types required vesicular trafficking, but only CD4+T cells required new protein synthesis to maintain high phosphorylation of STAT5. Two subunits of the IL-2 receptor, IL-2Rβ and IL-2Rγ, were twice as abundant in CD8+T cells than in CD4+T cells. Reduction of IL-2Rβ abundance by 50% was sufficient to convert CD8+T cells to a CD4+T cell–like signaling pattern and delay S phase entry. These results suggest that the larger pool of IL-2Rβ chains in CD8+T cells is required to sustain IL-2 signaling and contributes to the quantitatively greater proliferative response to IL-2 relative to that of CD4+T cells. This cell type–specific difference in IL-2Rβ abundance appears to tune responses, potentially preventing extensive, autoimmune proliferation of CD4+T cells, while still enabling sufficient proliferation of CD8+T cells to control viral infections.

    更新日期:2017-12-20
  • mGluR5 antagonism increases autophagy and prevents disease progression in the zQ175 mouse model of Huntington’s disease
    Sci. Signal. (IF 6.494) Pub Date : 2017-12-19
    Khaled S. Abd-Elrahman, Alison Hamilton, Shaunessy R. Hutchinson, Fang Liu, Ryan C. Russell, Stephen S. G. Ferguson

    Huntington’s disease (HD) is a neurodegenerative disease caused by an expansion in the huntingtin protein (also called Htt) that induces neuronal cell death with age. We found that the treatment of 12-month-old symptomatic heterozygous and homozygouszQ175huntingtin knockin mice for 12 weeks with CTEP, a negative allosteric modulator of metabotropic glutamate receptor 5 (mGluR5), reduced the size and number of huntingtin aggregates, attenuated caspase-3 activity, and reduced both neuronal apoptosis and neuronal loss in brain tissue. Both motor and cognitive impairments were improved in CTEP-treatedzQ175mice. The reduction in huntingtin protein aggregate burden by CTEP correlated with the activation of an autophagy pathway mediated by the kinase GSK3β, the transcription factor ZBTB16, and the autophagy factor ATG14. Inhibition of mGluR5 with CTEP also reduced the inhibitory phosphorylation of the autophagosome biogenesis–related kinase ULK1, increased the phosphorylation of the autophagy factor ATG13, and increased the abundance of the autophagy-related protein Beclin1 in homozygouszQ175mice. The findings suggest that mGluR5 antagonism may activate autophagy through convergent mechanisms to promote the clearance of mutant huntingtin aggregates and might be therapeutic in HD patients.

    更新日期:2017-12-20
  • Oncogenic PI3K promotes methionine dependency in breast cancer cells through the cystine-glutamate antiporter xCT
    Sci. Signal. (IF 6.494) Pub Date : 2017-12-19
    Evan C. Lien, Laura Ghisolfi, Renee C. Geck, John M. Asara, Alex Toker

    The precursor homocysteine is metabolized either through the methionine cycle to produce methionine or through the transsulfuration pathway to synthesize cysteine. Alternatively, cysteine can be obtained through uptake of its oxidized form, cystine. Many cancer cells exhibit methionine dependency such that their proliferation is impaired in growth media in which methionine is replaced by homocysteine. We showed that oncogenicPIK3CAand decreased expression ofSLC7A11, a gene that encodes a cystine transporter also known as xCT, correlated with increased methionine dependency in breast cancer cells. OncogenicPIK3CAwas sufficient to confer methionine dependency to mammary epithelial cells, partly by decreasing cystine uptake through the transcriptional and posttranslational inhibition of xCT. Manipulation of xCT activity altered the proliferation of breast cancer cells in methionine-deficient, homocysteine-containing media, suggesting that it functionally contributed to methionine dependency. We propose that concurrent with decreased cystine uptake through xCT,PIK3CAmutant cells use homocysteine through the transsulfuration pathway to synthesize cysteine. Consequently, less homocysteine is available to produce methionine, contributing to methionine dependency. These results indicate that oncogenicPIK3CAalters methionine and cysteine utilization, partly by inhibiting xCT to contribute to the methionine dependency phenotype in breast cancer cells.

    更新日期:2017-12-20
  • Papers of note in Science Translational Medicine 9 (420)
    Sci. Signal. (IF 6.494) Pub Date : 2017-12-19
    Leslie K. Ferrarelli

    This week’s articles describe ways to treat scleroderma and schizophrenia.

    更新日期:2017-12-20
  • Papers of note in Nature 552 (7684)
    Sci. Signal. (IF 6.494) Pub Date : 2017-12-19
    John F. Foley

    This week’s articles showed that enhancing a mitochondrial stress response reduced amyloid aggregation in mice; solved the structure of the ion channel TRPM4; found a role for NOTCH1 in the assembly of adherens junctions and endothelial barrier maintenance; and showed that RNA polymerase III limits life span in worms and flies.

    更新日期:2017-12-20
  • Papers of note in Science 358 (6369)
    Sci. Signal. (IF 6.494) Pub Date : 2017-12-19
    Annalisa M. VanHook

    This week’s articles explain why broad-leaved plants are susceptible to a microbial toxin that does not affect monocots; identify the enzymes that detyrosinate tubulin; and present synthetic biological systems for recording environmental signals and for translating a biochemical reaction into dynamic cellular behavior.

    更新日期:2017-12-20
  • Highlight: IL-2 receptor signaling
    Sci. Signal. (IF 6.494) Pub Date : 2017-12-19
    John F. Foley

    Two papers reveal the consequences of altered interleukin-2 receptor signaling in T lymphocytes.

    更新日期:2017-12-20
  • Altered homeostasis and development of regulatory T cell subsets represent an IL-2R–dependent risk for diabetes in NOD mice
    Sci. Signal. (IF 6.494) Pub Date : 2017-12-19
    Connor J. Dwyer, Allison L. Bayer, Carmen Fotino, Liping Yu, Cecilia Cabello-Kindelan, Natasha C. Ward, Kevin H. Toomer, Zhibin Chen, Thomas R. Malek

    The cytokine interleukin-2 (IL-2) is critical for the functions of regulatory T cells (Tregs). The contribution of polymorphisms in the gene encoding the IL-2 receptor α subunit (IL2RA), which are associated with type 1 diabetes, is difficult to determine because autoimmunity depends on variations in multiple genes, where the contribution of any one gene product is small. We investigated the mechanisms whereby a modest reduction in IL-2R signaling selectively in T lymphocytes influenced the development of diabetes in the NOD mouse model. The sensitivity of IL-2R signaling was reduced by about two- to threefold in Tregsfrom mice that coexpressed wild-type IL-2Rβ and a mutant subunit (IL-2RβY3) with reduced signaling (designated NOD-Y3). Male and female NOD-Y3 mice exhibited accelerated diabetes onset due to intrinsic effects on multiple activities in Tregs. Bone marrow chimera and adoptive transfer experiments demonstrated that IL-2RβY3Tregsresulted in impaired homeostasis of lymphoid-residing central Tregsand inefficient development of highly activated effector Tregsand that they were less suppressive. Pancreatic IL-2RβY3Tregsshowed impaired development into IL-10–secreting effector Tregs. The pancreatic lymph nodes and pancreases of NOD-Y3 mice had increased numbers of antigen-experienced CD4+effector T cells, which was largely due to impaired Tregs, because adoptively transferred pancreatic autoantigen–specific CD4+Foxp3−T cells from NOD-Y3 mice did not accelerate diabetes in NOD.SCID recipients. Our study indicates that the primary defect associated with chronic, mildly reduced IL-2R signaling is due to impaired Tregsthat cannot effectively produce and maintain highly functional tissue-seeking effector Tregsubsets.

    更新日期:2017-12-20
  • Aging impairs both primary and secondary RIG-I signaling for interferon induction in human monocytes
    Sci. Signal. (IF 6.494) Pub Date : 2017-12-12
    Ryan D. Molony, Jenny T. Nguyen, Yong Kong, Ruth R. Montgomery, Albert C. Shaw, Akiko Iwasaki

    Adults older than 65 account for most of the deaths caused by respiratory influenza A virus (IAV) infections, but the underlying mechanisms for this susceptibility are poorly understood. IAV RNA is detected by the cytosolic sensor retinoic acid–inducible gene I (RIG-I), which induces the production of type I interferons (IFNs) that curtail the spread of the virus and promote the elimination of infected cells. We have previously identified a marked defect in the IAV-inducible secretion of type I IFNs, but not proinflammatory cytokines, in monocytes from older (>65 years) healthy human donors. We found that monocytes from older adults exhibited decreased abundance of the adaptor protein TRAF3 (tumor necrosis factor receptor–associated factor 3) because of its increased proteasomal degradation with age, thereby impairing the primary RIG-I signaling pathway for the induction of type I IFNs. We determined that monocytes from older adults also failed to effectively stimulate the production of the IFN regulatory transcription factor IRF8, which compromised IFN induction through secondary RIG-I signaling. IRF8 played a central role in IFN induction in monocytes, because knocking down IRF8 in monocytes from younger adults was sufficient to replicate the IFN defects observed in monocytes from older adults, whereas restoring IRF8 expression in older adult monocytes was sufficient to restore RIG-I–induced IFN responses. Aging thus compromises both the primary and secondary RIG-I signaling pathways that govern expression of type I IFN genes, thereby impairing antiviral resistance to IAV.

    更新日期:2017-12-14
  • C-reactive protein promotes bone destruction in human myeloma through the CD32–p38 MAPK–Twist axis
    Sci. Signal. (IF 6.494) Pub Date : 2017-12-12
    Jing Yang, Zhiqiang Liu, Huan Liu, Jin He, Jianling Yang, Pei Lin, Qiang Wang, Juan Du, Wencai Ma, Zheng Yin, Eric Davis, Robert Z. Orlowski, Jian Hou, Qing Yi

    Bone destruction is a hallmark of myeloma and affects 80% of patients. Myeloma cells promote bone destruction by activating osteoclasts. In investigating the underlying mechanism, we found that C-reactive protein (CRP), a protein secreted in increased amounts by hepatocytes in response to myeloma-derived cytokines, activated myeloma cells to promote osteoclastogenesis and bone destruction in vivo. In mice bearing human bone grafts and injected with multiple myeloma cells, CRP bound to surface CD32 (also known as FcγRII) on myeloma cells, which activated a pathway mediated by the kinase p38 MAPK and the transcription factor Twist that enhanced the cells’ secretion of osteolytic cytokines. Furthermore, analysis of clinical samples from newly diagnosed myeloma patients revealed a positive correlation between the amount of serum CRP and the number of osteolytic bone lesions. These findings establish a mechanism by which myeloma cells are activated to promote bone destruction and suggest that CRP may be targeted to prevent or treat myeloma-associated bone disease in patients.

    更新日期:2017-12-14
  • Paper of note in Science Translational Medicine 9 (419)
    Sci. Signal. (IF 6.494) Pub Date : 2017-12-12
    Leslie K. Ferrarelli

    This week’s article describes a way to potentially reduce neurodegeneration in patients with Huntington’s disease.

    更新日期:2017-12-14
  • Papers of note in Nature 552 (7683)
    Sci. Signal. (IF 6.494) Pub Date : 2017-12-12
    Annalisa M. VanHook

    This week’s articles highlight a potential therapeutic target for fibrosis; parasite receptors that contribute to malaria; a potential drawback of PD-1 inhibition for cancer immunotherapy; a noncoding RNA that regulates ribosome biogenesis; and a structural analysis of substrate binding by the kinase PINK1.

    更新日期:2017-12-14
  • Papers of note in Science 358 (6368)
    Sci. Signal. (IF 6.494) Pub Date : 2017-12-12
    Annalisa M. VanHook

    This week’s articles report that inhibiting the ion channel TRPC5 prevents the loss of podocytes in rat models of kidney disease.

    更新日期:2017-12-14
  • Generating heat through Ca2+ cycling
    Sci. Signal. (IF 6.494) Pub Date : 2017-12-12
    Wei Wong

    Beige fat regulates whole-body energy homeostasis by cycling Ca2+through RyR2 and SERCA2b.

    更新日期:2017-12-14
  • RhoB controls the Rab11-mediated recycling and surface reappearance of LFA-1 in migrating T lymphocytes
    Sci. Signal. (IF 6.494) Pub Date : 2017-12-12
    Malin Samuelsson, Katarzyna Potrzebowska, Janne Lehtonen, Jason P. Beech, Ekatarina Skorova, Heli Uronen-Hansson, Lena Svensson

    The regulation of cell adhesion and motility is complex and requires the intracellular trafficking of integrins to and from sites of cell adhesion, especially in fast-moving cells such as leukocytes. The Rab family of guanosine triphosphatases (GTPases) is essential for vesicle transport, and vesicles mediate intracellular integrin trafficking. We showed that RhoB regulates the vesicular transport of the integrin LFA-1 along the microtubule network in migrating T lymphocytes. Impairment in RhoB function resulted in the accumulation of both LFA-1 and the recycling endosomal marker Rab11 at the rear of migrating T lymphocytes and decreased the association between these molecules. T lymphocytes lacking functional RhoB exhibited impaired recycling and subsequently decreased surface amounts of LFA-1, leading to reduced T cell adhesion and migration mediated by the cell adhesion molecule ICAM-1 (intercellular adhesion molecule–1). We propose that vesicle-associated RhoB is a regulator of the Rab11-mediated recycling of LFA-1 to the cell surface, an event that is necessary for T lymphocyte motility.

    更新日期:2017-12-14
  • Subtle modifications to oxytocin produce ligands that retain potency and improved selectivity across species
    Sci. Signal. (IF 6.494) Pub Date : 2017-12-05
    Markus Muttenthaler, Åsa Andersson, Irina Vetter, Rohit Menon, Marta Busnelli, Lotten Ragnarsson, Christian Bergmayr, Sarah Arrowsmith, Jennifer R. Deuis, Han Sheng Chiu, Nathan J. Palpant, Margaret O’Brien, Terry J. Smith, Susan Wray, Inga D. Neumann, Christian W. Gruber, Richard J. Lewis, Paul F. Alewood

    Oxytocin and vasopressin mediate various physiological functions that are important for osmoregulation, reproduction, cardiovascular function, social behavior, memory, and learning through four G protein–coupled receptors that are also implicated in high-profile disorders. Targeting these receptors is challenging because of the difficulty in obtaining ligands that retain selectivity across rodents and humans for translational studies. We identified a selective and more stable oxytocin receptor (OTR) agonist by subtly modifying the pharmacophore framework of human oxytocin and vasopressin. [Se-Se]-oxytocin-OH displayed similar potency to oxytocin but improved selectivity for OTR, an effect that was retained in mice. Centrally infused [Se-Se]-oxytocin-OH potently reversed social fear in mice, confirming that this action was mediated by OTR and not by V1a or V1b vasopressin receptors. In addition, [Se-Se]-oxytocin-OH produced a more regular contraction pattern than did oxytocin in a preclinical labor induction and augmentation model using myometrial strips from cesarean sections. [Se-Se]-oxytocin-OH had no activity in human cardiomyocytes, indicating a potentially improved safety profile and therapeutic window compared to those of clinically used oxytocin. In conclusion, [Se-Se]-oxytocin-OH is a novel probe for validating OTR as a therapeutic target in various biological systems and is a promising new lead for therapeutic development. Our medicinal chemistry approach may also be applicable to other peptidergic signaling systems with similar selectivity issues.

    更新日期:2017-12-12
  • HemITAM: A single tyrosine motif that packs a punch
    Sci. Signal. (IF 6.494) Pub Date : 2017-12-05
    Björn Bauer, Alexander Steinle

    Innate immune cells sense danger through a plethora of germline-encoded receptors that recognize pathogen-associated molecular patterns (PAMPs) or cellular molecules that are exposed only by stressed, infected, malignant, or dead cells. Many of these danger-sensing receptors belong to the C-type lectin-like superfamily (CLSF) and therefore are called C-type lectin-like receptors (CTLRs). Certain activating CTLRs, namely, CLEC-2, Dectin-1, DNGR-1, NKp80, and NKp65, which are encoded by genes that are clustered together in a subregion of the mammalian natural killer gene complex (NKC), use a single copy tyrosine signaling module termed the hemi-immunoreceptor tyrosine-based activation motif (hemITAM). These hemITAM-bearing CTLRs are present on myeloid cells and innate lymphocytes and stimulate various functions, such as phagocytosis, cytokine production, and cytotoxicity. Proximal signaling mechanisms involve the tyrosine phosphorylation of the hemITAM and the subsequent activation of the kinase Syk. Signaling and Syk recruitment by the hemITAM appear to be tuned by variable amino acids within or near the hemITAM, which give rise to differences in downstream signaling events and diverging functional outcomes among hemITAM-bearing receptors.

    更新日期:2017-12-12
  • The receptor tyrosine kinase EphA2 promotes glutamine metabolism in tumors by activating the transcriptional coactivators YAP and TAZ
    Sci. Signal. (IF 6.494) Pub Date : 2017-12-05
    Deanna N. Edwards, Verra M. Ngwa, Shan Wang, Eileen Shiuan, Dana M. Brantley-Sieders, Laura C. Kim, Albert B. Reynolds, Jin Chen

    Malignant tumors reprogram cellular metabolism to support cancer cell proliferation and survival. Although most cancers depend on a high rate of aerobic glycolysis, many cancer cells also display addiction to glutamine. Glutamine transporters and glutaminase activity are critical for glutamine metabolism in tumor cells. We found that the receptor tyrosine kinase EphA2 activated the TEAD family transcriptional coactivators YAP and TAZ (YAP/TAZ), likely in a ligand-independent manner, to promote glutamine metabolism in cells and mouse models of HER2-positive breast cancer. Overexpression of EphA2 induced the nuclear accumulation of YAP and TAZ and increased the expression of YAP/TAZ target genes. Inhibition of the GTPase Rho or the kinase ROCK abolished EphA2-dependent YAP/TAZ nuclear localization. SilencingYAPorTAZsubstantially reduced the amount of intracellular glutamate through decreased expression ofSLC1A5andGLS, respectively, genes that encode proteins that promote glutamine uptake and metabolism. The regulatory DNA elements of bothSLC1A5andGLScontain TEAD binding sites and were bound by TEAD4 in an EphA2-dependent manner. In patient breast cancer tissues,EphA2expression positively correlated with that ofYAPandTAZ, as well as that ofGLSandSLC1A5. Although high expression ofEphA2predicted enhanced metastatic potential and poor patient survival, it also rendered HER2-positive breast cancer cells more sensitive to glutaminase inhibition. The findings define a previously unknown mechanism of EphA2-mediated glutaminolysis through YAP/TAZ activation in HER2-positive breast cancer and identify potential therapeutic targets in patients.

    更新日期:2017-12-12
  • Papers of note in Science Translational Medicine 9 (418)
    Sci. Signal. (IF 6.494) Pub Date : 2017-12-05
    Leslie K. Ferrarelli

    This week’s articles describe a way to treat or prevent pulmonary distress and a way to boost treatments against anemia.

    更新日期:2017-12-12
  • Papers of note in Nature 551 (7682)
    Sci. Signal. (IF 6.494) Pub Date : 2017-12-05
    Annalisa M. VanHook

    This week’s articles highlight proteostasis in the germ line, tumor cell survival in high-oxygen environments, and gut symbiont metabolites that affect intestinal physiology and systemic immunity.

    更新日期:2017-12-12
  • Papers of note in Science 358 (6367)
    Sci. Signal. (IF 6.494) Pub Date : 2017-12-05
    Annalisa M. VanHook

    This week’s articles focus on cross-talk between lung tumors and bone, the druggable kinome, and the structure of a DNA damage sensor.

    更新日期:2017-12-12
  • Stimulating NETosis instead of mitosis
    Sci. Signal. (IF 6.494) Pub Date : 2017-12-05
    Annalisa M. VanHook

    Cell cycle regulators control the production of neutrophil extracellular traps.

    更新日期:2017-12-12
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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