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  • 1
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    Commensal-dendritic-cell interaction specifies a unique protective skin immune signature (2014)
    Nature Publishing Group (NPG)
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    Publikationsdatum: 2014-12-30
    Beschreibung: The skin represents the primary interface between the host and the environment. This organ is also home to trillions of microorganisms that play an important role in tissue homeostasis and local immunity. Skin microbial communities are highly diverse and can be remodelled over time or in response to environmental challenges. How, in the context of this complexity, individual commensal microorganisms may differentially modulate skin immunity and the consequences of these responses for tissue physiology remains unclear. Here we show that defined commensals dominantly affect skin immunity and identify the cellular mediators involved in this specification. In particular, colonization with Staphylococcus epidermidis induces IL-17A(+) CD8(+) T cells that home to the epidermis, enhance innate barrier immunity and limit pathogen invasion. Commensal-specific T-cell responses result from the coordinated action of skin-resident dendritic cell subsets and are not associated with inflammation, revealing that tissue-resident cells are poised to sense and respond to alterations in microbial communities. This interaction may represent an evolutionary means by which the skin immune system uses fluctuating commensal signals to calibrate barrier immunity and provide heterologous protection against invasive pathogens. These findings reveal that the skin immune landscape is a highly dynamic environment that can be rapidly and specifically remodelled by encounters with defined commensals, findings that have profound implications for our understanding of tissue-specific immunity and pathologies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667810/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667810/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Naik, Shruti -- Bouladoux, Nicolas -- Linehan, Jonathan L -- Han, Seong-Ji -- Harrison, Oliver J -- Wilhelm, Christoph -- Conlan, Sean -- Himmelfarb, Sarah -- Byrd, Allyson L -- Deming, Clayton -- Quinones, Mariam -- Brenchley, Jason M -- Kong, Heidi H -- Tussiwand, Roxanne -- Murphy, Kenneth M -- Merad, Miriam -- Segre, Julia A -- Belkaid, Yasmine -- R01 CA173861/CA/NCI NIH HHS/ -- R01 CA190400/CA/NCI NIH HHS/ -- U01 AI095611/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2015 Apr 2;520(7545):104-8. doi: 10.1038/nature14052. Epub 2015 Jan 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Immunity at Barrier Sites Initiative, National Institute of Allergy and Infectious Diseases, NIH, Bethesda 20892, USA [2] Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland 20892, USA. ; Translational and Functional Genomics Branch, National Human Genome Research Institute, Bethesda, Maryland 20892, USA. ; 1] Immunity at Barrier Sites Initiative, National Institute of Allergy and Infectious Diseases, NIH, Bethesda 20892, USA [2] Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland 20892, USA [3] Translational and Functional Genomics Branch, National Human Genome Research Institute, Bethesda, Maryland 20892, USA. ; Bioinformatics and Computational Bioscience Branch, National Institute of Allergy and Infectious Diseases, NIH Bethesda, Maryland 20892, USA. ; 1] Immunity at Barrier Sites Initiative, National Institute of Allergy and Infectious Diseases, NIH, Bethesda 20892, USA [2] Immunopathogenesis Section, Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, NIH Bethesda, Maryland 20892, USA. ; Dermatology Branch, National Cancer Institute, NIH Bethesda, Maryland 20892, USA. ; Howard Hughes Medical Institute, Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; Department of Oncological Sciences, Tisch Cancer Institute and Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25539086" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Antigens, Bacterial/immunology ; CD8-Positive T-Lymphocytes/cytology/*immunology ; Dendritic Cells/cytology/*immunology ; Humans ; Immunity, Innate/immunology ; Interleukin-17/immunology ; Langerhans Cells/cytology/immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Primates ; Skin/cytology/*immunology/*microbiology ; Staphylococcus epidermidis/immunology ; Symbiosis/*immunology
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
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  • 2
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    Meikin is a conserved regulator of meiosis-I-specific kinetochore function (2014)
    Nature Publishing Group (NPG)
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    Publikationsdatum: 2014-12-24
    Beschreibung: The kinetochore is the crucial apparatus regulating chromosome segregation in mitosis and meiosis. Particularly in meiosis I, unlike in mitosis, sister kinetochores are captured by microtubules emanating from the same spindle pole (mono-orientation) and centromeric cohesion mediated by cohesin is protected in the following anaphase. Although meiotic kinetochore factors have been identified only in budding and fission yeasts, these molecules and their functions are thought to have diverged earlier. Therefore, a conserved mechanism for meiotic kinetochore regulation remains elusive. Here we have identified in mouse a meiosis-specific kinetochore factor that we termed MEIKIN, which functions in meiosis I but not in meiosis II or mitosis. MEIKIN plays a crucial role in both mono-orientation and centromeric cohesion protection, partly by stabilizing the localization of the cohesin protector shugoshin. These functions are mediated mainly by the activity of Polo-like kinase PLK1, which is enriched to kinetochores in a MEIKIN-dependent manner. Our integrative analysis indicates that the long-awaited key regulator of meiotic kinetochore function is Meikin, which is conserved from yeasts to humans.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Jihye -- Ishiguro, Kei-ichiro -- Nambu, Aya -- Akiyoshi, Bungo -- Yokobayashi, Shihori -- Kagami, Ayano -- Ishiguro, Tadashi -- Pendas, Alberto M -- Takeda, Naoki -- Sakakibara, Yogo -- Kitajima, Tomoya S -- Tanno, Yuji -- Sakuno, Takeshi -- Watanabe, Yoshinori -- England -- Nature. 2015 Jan 22;517(7535):466-71. doi: 10.1038/nature14097. Epub 2014 Dec 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Chromosome Dynamics, Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1Yayoi, Tokyo 113-0032, Japan. ; Instituto de Biologia Molecular y Celular del Cancer (CSIC-USAL), 37007 Salamanca, Spain. ; Center for Animal Resources and Development, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811 Japan. ; Laboratory for Chromosome Segregation, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25533956" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Cell Cycle Proteins/metabolism ; Centromere/metabolism ; Chromosomal Proteins, Non-Histone/deficiency/genetics/*metabolism ; *Conserved Sequence ; Female ; Humans ; Infertility/genetics/metabolism ; Kinetochores/*metabolism ; Male ; *Meiosis ; Mice ; Molecular Sequence Data ; Protein-Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins/metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Schizosaccharomyces pombe Proteins/metabolism
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
    Standort Signatur Erwartet Verfügbarkeit
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  • 3
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    Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury (2014)
    Nature Publishing Group (NPG)
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    Publikationsdatum: 2014-12-24
    Beschreibung: Broadly, tissue regeneration is achieved in two ways: by proliferation of common differentiated cells and/or by deployment of specialized stem/progenitor cells. Which of these pathways applies is both organ- and injury-specific. Current models in the lung posit that epithelial repair can be attributed to cells expressing mature lineage markers. By contrast, here we define the regenerative role of previously uncharacterized, rare lineage-negative epithelial stem/progenitor (LNEP) cells present within normal distal lung. Quiescent LNEPs activate a DeltaNp63 (a p63 splice variant) and cytokeratin 5 remodelling program after influenza or bleomycin injury in mice. Activated cells proliferate and migrate widely to occupy heavily injured areas depleted of mature lineages, at which point they differentiate towards mature epithelium. Lineage tracing revealed scant contribution of pre-existing mature epithelial cells in such repair, whereas orthotopic transplantation of LNEPs, isolated by a definitive surface profile identified through single-cell sequencing, directly demonstrated the proliferative capacity and multipotency of this population. LNEPs require Notch signalling to activate the DeltaNp63 and cytokeratin 5 program, and subsequent Notch blockade promotes an alveolar cell fate. Persistent Notch signalling after injury led to parenchymal 'micro-honeycombing' (alveolar cysts), indicative of failed regeneration. Lungs from patients with fibrosis show analogous honeycomb cysts with evidence of hyperactive Notch signalling. Our findings indicate that distinct stem/progenitor cell pools repopulate injured tissue depending on the extent of the injury, and the outcomes of regeneration or fibrosis may depend in part on the dynamics of LNEP Notch signalling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312207/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312207/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vaughan, Andrew E -- Brumwell, Alexis N -- Xi, Ying -- Gotts, Jeffrey E -- Brownfield, Doug G -- Treutlein, Barbara -- Tan, Kevin -- Tan, Victor -- Liu, Feng Chun -- Looney, Mark R -- Matthay, Michael A -- Rock, Jason R -- Chapman, Harold A -- F32 HL117600-01/HL/NHLBI NIH HHS/ -- R01 HL44712/HL/NHLBI NIH HHS/ -- U01 HL099995/HL/NHLBI NIH HHS/ -- U01 HL099999/HL/NHLBI NIH HHS/ -- U01 HL111054/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jan 29;517(7536):621-5. doi: 10.1038/nature14112. Epub 2014 Dec 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco (UCSF), San Francisco, California 94143, USA. ; Department of Biochemistry, Stanford University School of Medicine and Howard Hughes Medical Institute, Stanford, California 94305, USA. ; Max Planck Institute for Evolutionary Anthropology, Department of Evolutionary Genetics, Deutscher Platz 6, 04103 Leipzig, Germany. ; Department of Anatomy, School of Medicine, University of California, San Francisco (UCSF), San Francisco, California 94143, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25533958" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Bleomycin ; Cell Lineage ; Cell Proliferation ; Cell Separation ; Cysts/metabolism/pathology ; Epithelial Cells/*cytology/metabolism/*pathology ; Female ; Humans ; Keratin-5/metabolism ; Lung/*cytology/*pathology/physiology ; Lung Injury/chemically induced/*pathology/virology ; Male ; Mice ; Orthomyxoviridae Infections/pathology/virology ; Phosphoproteins/genetics/metabolism ; *Re-Epithelialization ; Receptors, Notch/metabolism ; Signal Transduction ; Stem Cell Transplantation ; Stem Cells/*cytology/metabolism ; Trans-Activators/genetics/metabolism
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
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  • 4
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    Large-scale discovery of novel genetic causes of developmental disorders (2014)
    Nature Publishing Group (NPG)
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    Publikationsdatum: 2014-12-24
    Beschreibung: Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Deciphering Developmental Disorders Study -- 098395/Wellcome Trust/United Kingdom -- 100140/Wellcome Trust/United Kingdom -- CZD/16/6/Chief Scientist Office/United Kingdom -- WT098051/Wellcome Trust/United Kingdom -- Department of Health/United Kingdom -- England -- Nature. 2015 Mar 12;519(7542):223-8. doi: 10.1038/nature14135. Epub 2014 Dec 24.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25533962" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Adolescent ; Animals ; Carrier Proteins/genetics ; Child ; Child, Preschool ; Chromosomal Proteins, Non-Histone/genetics ; Chromosome Aberrations ; DEAD-box RNA Helicases/genetics ; DNA-Binding Proteins/genetics ; Developmental Disabilities/*diagnosis/*genetics ; Dynamin I/genetics ; Exome/genetics ; Female ; Gene Expression Regulation, Developmental ; Genes, Dominant/genetics ; Genome, Human/genetics ; Great Britain ; Guanine Nucleotide Exchange Factors/genetics ; Homeodomain Proteins/genetics ; Humans ; Infant ; Infant, Newborn ; Male ; Mutation, Missense/genetics ; Nerve Tissue Proteins/genetics ; Nuclear Proteins/genetics ; Parents ; Phosphoproteins/genetics ; Polycomb Repressive Complex 1/genetics ; Protein Phosphatase 2/genetics ; Protein-Serine-Threonine Kinases/genetics ; Rare Diseases/genetics ; Transcription Factors/genetics ; Transposases/genetics ; Zebrafish/genetics
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
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  • 5
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    Dissecting neural differentiation regulatory networks through epigenetic footprinting (2014)
    Nature Publishing Group (NPG)
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    Publikationsdatum: 2014-12-24
    Beschreibung: Models derived from human pluripotent stem cells that accurately recapitulate neural development in vitro and allow for the generation of specific neuronal subtypes are of major interest to the stem cell and biomedical community. Notch signalling, particularly through the Notch effector HES5, is a major pathway critical for the onset and maintenance of neural progenitor cells in the embryonic and adult nervous system. Here we report the transcriptional and epigenomic analysis of six consecutive neural progenitor cell stages derived from a HES5::eGFP reporter human embryonic stem cell line. Using this system, we aimed to model cell-fate decisions including specification, expansion and patterning during the ontogeny of cortical neural stem and progenitor cells. In order to dissect regulatory mechanisms that orchestrate the stage-specific differentiation process, we developed a computational framework to infer key regulators of each cell-state transition based on the progressive remodelling of the epigenetic landscape and then validated these through a pooled short hairpin RNA screen. We were also able to refine our previous observations on epigenetic priming at transcription factor binding sites and suggest here that they are mediated by combinations of core and stage-specific factors. Taken together, we demonstrate the utility of our system and outline a general framework, not limited to the context of the neural lineage, to dissect regulatory circuits of differentiation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336237/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336237/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ziller, Michael J -- Edri, Reuven -- Yaffe, Yakey -- Donaghey, Julie -- Pop, Ramona -- Mallard, William -- Issner, Robbyn -- Gifford, Casey A -- Goren, Alon -- Xing, Jeffrey -- Gu, Hongcang -- Cacchiarelli, Davide -- Tsankov, Alexander M -- Epstein, Charles -- Rinn, John L -- Mikkelsen, Tarjei S -- Kohlbacher, Oliver -- Gnirke, Andreas -- Bernstein, Bradley E -- Elkabetz, Yechiel -- Meissner, Alexander -- F32 DK095537/DK/NIDDK NIH HHS/ -- HG006911/HG/NHGRI NIH HHS/ -- P01 GM099117/GM/NIGMS NIH HHS/ -- P01GM099117/GM/NIGMS NIH HHS/ -- U01 ES017155/ES/NIEHS NIH HHS/ -- U01ES017155/ES/NIEHS NIH HHS/ -- U54 HG006991/HG/NHGRI NIH HHS/ -- England -- Nature. 2015 Feb 19;518(7539):355-9. doi: 10.1038/nature13990. Epub 2014 Dec 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Ramat Aviv 6997801, Israel. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA [3] Center for Systems Biology and Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Applied Bioinformatics, Center for Bioinformatics and Quantitative Biology Center, University of Tubingen, Tubingen 72076, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25533951" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Binding Sites ; Cell Differentiation/*genetics ; Cell Lineage/genetics ; Embryonic Stem Cells/*cytology/metabolism ; Epigenesis, Genetic/*genetics ; Epigenomics/*methods ; Humans ; Neural Stem Cells/*cytology/*metabolism ; RNA, Small Interfering/analysis/genetics ; Reproducibility of Results ; Transcription Factors/metabolism ; Transcription, Genetic/genetics
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
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  • 6
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    Cell division: Hold on and let go (2014)
    Nature Publishing Group (NPG)
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    Publikationsdatum: 2014-12-24
    Beschreibung: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tachibana-Konwalski, Kikue -- England -- Nature. 2015 Jan 22;517(7535):441-2. doi: 10.1038/nature14087. Epub 2014 Dec 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 1030 Vienna, Austria.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25533954" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Chromosomal Proteins, Non-Histone/*metabolism ; *Conserved Sequence ; Female ; Humans ; Kinetochores/*metabolism ; Male ; *Meiosis
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
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  • 7
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    Folding of an intrinsically disordered protein by phosphorylation as a regulatory switch (2014)
    Nature Publishing Group (NPG)
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    Publikationsdatum: 2014-12-24
    Beschreibung: Intrinsically disordered proteins play important roles in cell signalling, transcription, translation and cell cycle regulation. Although they lack stable tertiary structure, many intrinsically disordered proteins undergo disorder-to-order transitions upon binding to partners. Similarly, several folded proteins use regulated order-to-disorder transitions to mediate biological function. In principle, the function of intrinsically disordered proteins may be controlled by post-translational modifications that lead to structural changes such as folding, although this has not been observed. Here we show that multisite phosphorylation induces folding of the intrinsically disordered 4E-BP2, the major neural isoform of the family of three mammalian proteins that bind eIF4E and suppress cap-dependent translation initiation. In its non-phosphorylated state, 4E-BP2 interacts tightly with eIF4E using both a canonical YXXXXLPhi motif (starting at Y54) that undergoes a disorder-to-helix transition upon binding and a dynamic secondary binding site. We demonstrate that phosphorylation at T37 and T46 induces folding of residues P18-R62 of 4E-BP2 into a four-stranded beta-domain that sequesters the helical YXXXXLPhi motif into a partly buried beta-strand, blocking its accessibility to eIF4E. The folded state of pT37pT46 4E-BP2 is weakly stable, decreasing affinity by 100-fold and leading to an order-to-disorder transition upon binding to eIF4E, whereas fully phosphorylated 4E-BP2 is more stable, decreasing affinity by a factor of approximately 4,000. These results highlight stabilization of a phosphorylation-induced fold as the essential mechanism for phospho-regulation of the 4E-BP:eIF4E interaction and exemplify a new mode of biological regulation mediated by intrinsically disordered proteins.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bah, Alaji -- Vernon, Robert M -- Siddiqui, Zeba -- Krzeminski, Mickael -- Muhandiram, Ranjith -- Zhao, Charlie -- Sonenberg, Nahum -- Kay, Lewis E -- Forman-Kay, Julie D -- MOP-114985/Canadian Institutes of Health Research/Canada -- MOP-119579/Canadian Institutes of Health Research/Canada -- England -- Nature. 2015 Mar 5;519(7541):106-9. doi: 10.1038/nature13999. Epub 2014 Dec 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Molecular Structure and Function Program, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada [2] Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Molecular Structure and Function Program, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada. ; 1] Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3G 1Y6, Canada. ; 1] Molecular Structure and Function Program, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada [2] Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada [3] Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada [4] Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25533957" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Binding Sites ; Eukaryotic Initiation Factor-4E/*chemistry/*metabolism ; Eukaryotic Initiation Factors/*chemistry/*metabolism ; Humans ; Intrinsically Disordered Proteins/*chemistry/*metabolism ; Models, Molecular ; Nuclear Magnetic Resonance, Biomolecular ; Phosphorylation ; Protein Binding ; *Protein Folding ; Protein Structure, Secondary ; Signal Transduction
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
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  • 8
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    Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity (2014)
    Nature Publishing Group (NPG)
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    Publikationsdatum: 2014-12-24
    Beschreibung: Obesity is an increasingly prevalent disease regulated by genetic and environmental factors. Emerging studies indicate that immune cells, including monocytes, granulocytes and lymphocytes, regulate metabolic homeostasis and are dysregulated in obesity. Group 2 innate lymphoid cells (ILC2s) can regulate adaptive immunity and eosinophil and alternatively activated macrophage responses, and were recently identified in murine white adipose tissue (WAT) where they may act to limit the development of obesity. However, ILC2s have not been identified in human adipose tissue, and the mechanisms by which ILC2s regulate metabolic homeostasis remain unknown. Here we identify ILC2s in human WAT and demonstrate that decreased ILC2 responses in WAT are a conserved characteristic of obesity in humans and mice. Interleukin (IL)-33 was found to be critical for the maintenance of ILC2s in WAT and in limiting adiposity in mice by increasing caloric expenditure. This was associated with recruitment of uncoupling protein 1 (UCP1)(+) beige adipocytes in WAT, a process known as beiging or browning that regulates caloric expenditure. IL-33-induced beiging was dependent on ILC2s, and IL-33 treatment or transfer of IL-33-elicited ILC2s was sufficient to drive beiging independently of the adaptive immune system, eosinophils or IL-4 receptor signalling. We found that ILC2s produce methionine-enkephalin peptides that can act directly on adipocytes to upregulate Ucp1 expression in vitro and that promote beiging in vivo. Collectively, these studies indicate that, in addition to responding to infection or tissue damage, ILC2s can regulate adipose function and metabolic homeostasis in part via production of enkephalin peptides that elicit beiging.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447235/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447235/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brestoff, Jonathan R -- Kim, Brian S -- Saenz, Steven A -- Stine, Rachel R -- Monticelli, Laurel A -- Sonnenberg, Gregory F -- Thome, Joseph J -- Farber, Donna L -- Lutfy, Kabirullah -- Seale, Patrick -- Artis, David -- 2-P30 CA016520/CA/NCI NIH HHS/ -- AI061570/AI/NIAID NIH HHS/ -- AI074878/AI/NIAID NIH HHS/ -- AI095466/AI/NIAID NIH HHS/ -- AI095608/AI/NIAID NIH HHS/ -- AI097333/AI/NIAID NIH HHS/ -- AI102942/AI/NIAID NIH HHS/ -- DP2 OD007288/OD/NIH HHS/ -- DP2OD007288/OD/NIH HHS/ -- DP5 OD012116/OD/NIH HHS/ -- DP5OD012116/OD/NIH HHS/ -- F30 AI112023/AI/NIAID NIH HHS/ -- F30-AI112023/AI/NIAID NIH HHS/ -- F31 AG047003/AG/NIA NIH HHS/ -- F31AG047003/AG/NIA NIH HHS/ -- K08 AR065577/AR/NIAMS NIH HHS/ -- KL2-RR024132/RR/NCRR NIH HHS/ -- P01 AI106697/AI/NIAID NIH HHS/ -- P01AI06697/AI/NIAID NIH HHS/ -- P30 AR057217/AR/NIAMS NIH HHS/ -- P30 DK019525/DK/NIDDK NIH HHS/ -- P30-DK050306/DK/NIDDK NIH HHS/ -- P30DK19525/DK/NIDDK NIH HHS/ -- R01 AI061570/AI/NIAID NIH HHS/ -- R01 AI074878/AI/NIAID NIH HHS/ -- R01 AI095466/AI/NIAID NIH HHS/ -- R01 AI097333/AI/NIAID NIH HHS/ -- R01 AI102942/AI/NIAID NIH HHS/ -- T32 AI060516/AI/NIAID NIH HHS/ -- T32-AI007532/AI/NIAID NIH HHS/ -- T32-AI060516/AI/NIAID NIH HHS/ -- U01 AI095608/AI/NIAID NIH HHS/ -- England -- Nature. 2015 Mar 12;519(7542):242-6. doi: 10.1038/nature14115. Epub 2014 Dec 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Jill Roberts Institute for Research in IBD, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, New York 10021, USA [2] Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Institute for Diabetes, Obesity and Metabolism, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Jill Roberts Institute for Research in IBD, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, New York 10021, USA. ; 1] Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York 10032, USA [2] Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York 10032, USA. ; 1] Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York 10032, USA [2] Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York 10032, USA [3] Department of Surgery, Columbia University Medical Center, New York, New York 10032, USA. ; Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, California 91766, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25533952" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Adipocytes/cytology/drug effects ; Adipose Tissue, White/*cytology/*immunology ; Animals ; Energy Metabolism/immunology ; Enkephalin, Methionine/biosynthesis/metabolism ; Eosinophils/immunology/metabolism ; Female ; Homeostasis/drug effects ; Humans ; Immunity, Innate/*immunology ; Interleukins/immunology/pharmacology ; Ion Channels/metabolism ; Lymphocytes/cytology/immunology/*physiology ; Male ; Mice ; Mitochondrial Proteins/metabolism ; Obesity/*immunology/pathology ; Receptors, Interleukin-4/immunology/metabolism
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
    Standort Signatur Erwartet Verfügbarkeit
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    Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant (2014)
    Nature Publishing Group (NPG)
    Details
    Publikationsdatum: 2014-12-24
    Beschreibung: The orexin (also known as hypocretin) G protein-coupled receptors (GPCRs) respond to orexin neuropeptides in the central nervous system to regulate sleep and other behavioural functions in humans. Defects in orexin signalling are responsible for the human diseases of narcolepsy and cataplexy; inhibition of orexin receptors is an effective therapy for insomnia. The human OX2 receptor (OX2R) belongs to the beta branch of the rhodopsin family of GPCRs, and can bind to diverse compounds including the native agonist peptides orexin-A and orexin-B and the potent therapeutic inhibitor suvorexant. Here, using lipid-mediated crystallization and protein engineering with a novel fusion chimaera, we solved the structure of the human OX2R bound to suvorexant at 2.5 A resolution. The structure reveals how suvorexant adopts a pi-stacked horseshoe-like conformation and binds to the receptor deep in the orthosteric pocket, stabilizing a network of extracellular salt bridges and blocking transmembrane helix motions necessary for activation. Computational docking suggests how other classes of synthetic antagonists may interact with the receptor at a similar position in an analogous pi-stacked fashion. Elucidation of the molecular architecture of the human OX2R expands our understanding of peptidergic GPCR ligand recognition and will aid further efforts to modulate orexin signalling for therapeutic ends.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yin, Jie -- Mobarec, Juan Carlos -- Kolb, Peter -- Rosenbaum, Daniel M -- England -- Nature. 2015 Mar 12;519(7542):247-50. doi: 10.1038/nature14035. Epub 2014 Dec 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biophysics, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Department of Pharmaceutical Chemistry, Philipps-University Marburg, 35032 Marburg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25533960" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Azepines/*chemistry/metabolism/*pharmacology ; Crystallography, X-Ray ; Humans ; Molecular Docking Simulation ; *Orexin Receptor Antagonists ; Orexin Receptors/*chemistry/metabolism ; Protein Conformation ; Receptors, G-Protein-Coupled/antagonists & inhibitors/chemistry/metabolism ; Recombinant Fusion Proteins/chemistry/metabolism ; Sleep Initiation and Maintenance Disorders/drug therapy ; Triazoles/*chemistry/metabolism/*pharmacology
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
    Standort Signatur Erwartet Verfügbarkeit
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  • 10
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    A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol (2014)
    Nature Publishing Group (NPG)
    Details
    Publikationsdatum: 2014-12-24
    Beschreibung: Resveratrol is reported to extend lifespan and provide cardio-neuro-protective, anti-diabetic, and anti-cancer effects by initiating a stress response that induces survival genes. Because human tyrosyl transfer-RNA (tRNA) synthetase (TyrRS) translocates to the nucleus under stress conditions, we considered the possibility that the tyrosine-like phenolic ring of resveratrol might fit into the active site pocket to effect a nuclear role. Here we present a 2.1 A co-crystal structure of resveratrol bound to the active site of TyrRS. Resveratrol nullifies the catalytic activity and redirects TyrRS to a nuclear function, stimulating NAD(+)-dependent auto-poly-ADP-ribosylation of poly(ADP-ribose) polymerase 1 (PARP1). Downstream activation of key stress signalling pathways are causally connected to TyrRS-PARP1-NAD(+) collaboration. This collaboration is also demonstrated in the mouse, and is specifically blocked in vivo by a resveratrol-displacing tyrosyl adenylate analogue. In contrast to functionally diverse tRNA synthetase catalytic nulls created by alternative splicing events that ablate active sites, here a non-spliced TyrRS catalytic null reveals a new PARP1- and NAD(+)-dependent dimension to the physiological mechanism of resveratrol.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368482/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368482/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sajish, Mathew -- Schimmel, Paul -- CA92577/CA/NCI NIH HHS/ -- R01 CA092577/CA/NCI NIH HHS/ -- England -- Nature. 2015 Mar 19;519(7543):370-3. doi: 10.1038/nature14028. Epub 2014 Dec 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Skaggs Institute for Chemical Biology, The Scripps Laboratories for tRNA Synthetase Research, Department of Molecular and Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. ; 1] The Skaggs Institute for Chemical Biology, The Scripps Laboratories for tRNA Synthetase Research, Department of Molecular and Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA [2] The Scripps Florida Research Institute, 130 Scripps Way, Jupiter, Florida 33458, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25533949" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Alternative Splicing ; Animals ; Biocatalysis/drug effects ; Catalytic Domain ; Cell Nucleus/enzymology ; Crystallography, X-Ray ; Culture Media, Serum-Free ; Enzyme Activation/drug effects ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Models, Molecular ; Poly Adenosine Diphosphate Ribose/metabolism ; Poly(ADP-ribose) Polymerases/chemistry/*metabolism ; Protein Conformation ; Signal Transduction/drug effects ; Sirtuin 1/metabolism ; Sirtuins/metabolism ; Stilbenes/antagonists & inhibitors/chemistry/*pharmacology ; Tyrosine-tRNA Ligase/*antagonists & inhibitors/chemistry/*metabolism
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
    Standort Signatur Erwartet Verfügbarkeit
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