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STAT1 is an indispensable component of a heterotrimer (ISGF3) and a STAT1 homodimer (GAF) that function as transcription regulators in type 1 and type 2 interferon signaling, respectively. To investigate the importance of STAT1-cooperative DNA binding, we generated gene-targeted mice expressing cooperativity-deficient STAT1 with alanine substituted for Phe77. Neither ISGF3 nor GAF bound DNA cooperatively in the STAT1F77A mouse strain, but type 1 and type 2 interferon responses were affected differently. Type 2 interferon-mediated transcription and antibacterial immunity essentially disappeared owing to defective promoter recruitment of GAF. In contrast, STAT1 recruitment to ISGF3 binding sites and type 1 interferon-dependent responses, including antiviral protection, remained intact. We conclude that STAT1 cooperativity is essential for its biological activity and underlies the cellular responses to type 2, but not type 1 interferon.. null, 15.
1] School of Life Sciences, University of Nottingham, Nottingham, UK. [2].pmxmb2@nottingham.ac.ukUniversity of NottinghamBIOMD0000000500STAT1 is an indispensable component of a heterotrimer (ISGF3) and a STAT1 homodimer (GAF) that function as transcription regulators in type 1 and type 2 interferon signaling, respectively. To investigate the importance of STAT1-cooperative DNA binding, we generated gene-targeted mice expressing cooperativity-deficient STAT1 with alanine substituted for Phe77. Neither ISGF3 nor GAF bound DNA cooperatively in the STAT1F77A mouse strain, but type 1 and type 2 interferon responses were affected differently. Type 2 interferon-mediated transcription and antibacterial immunity essentially disappeared owing to defective promoter recruitment of GAF. In contrast, STAT1 recruitment to ISGF3 binding sites and type 1 interferon-dependent responses, including antiviral protection, remained intact. We conclude that STAT1 cooperativity is essential for its biological activity and underlies the cellular responses to type 2, but not type 1 interferon.STAT1-cooperative DNA binding distinguishes type 1 from type 2 interferon signaling.Begitt Andreas A, Droescher Mathias M, Meyer Thomas T, Schmid Christoph D CD, Baker Michelle M, Antunes Filipa F, Knobeloch Klaus-Peter KP, Owen Markus R MR, Naumann Ronald R, Decker Thomas T, Vinkemeier Uwe Upolymer, macromolecules, (+)-germacrene A synthase activity, Kunststoff., structure-specific DNA binding, CANDF7, polymer molecule, STAT91, 2010005J02Rik, 6-trans-farnesyl-diphosphate diphosphate-lyase [(+)-germacrene-A-forming] activity, plasmid binding, 2-trans, XStat1, gas, GAST, (+)-(10R)-germacrene A synthase activity, polymers, DD6G4-4, PA1, microtubule/chromatin interaction, Polymer, IMD31B, ISGF-3, IMD31C, IMD31A, C16orf53, AA408197, structure specific DNA binding, germacrene A synthase activity, GAS, 6-trans-farnesyl-diphosphate diphosphate-lyase (germacrene-A-forming) activity, macromoleculeLaboratory, STAT91, Mus domesticus, Adf2, CASP-14, XStat1, Antiviral, Antiviral Agent, House Mouse, Cell Type, Generation, A, Bind, Targeting, Immune Processes, thymus nucleic acid, Immune Responses, CANDF7, SYNS3, Swiss Mice, alanina, alanine, ecotype, DNA-dependent, HBGF-9, Immune, signaling process, AA408197, HAI, Double-Stranded DNA, deoxyribonucleic acids, house mouse, DNAn, CG33261, transcription from bacterial-type RNA polymerase promoter, single organism signaling, LOINC Axis 1, homodimer, Dependent Dressing, Interferon., IRF-9, Bound, DNA-dependent transcription, Process, functional failure, aberrant, Recruitment, mouse, Irf-9, Double-Stranded, Binding, (Deoxyribonucleotide)n+m, Glia-activating factor, Neither Case or Control Status, Adf-2, GAF, Gaf, Mini-ICE, Normal Cell, Cellular, cultivar, failure, HBFG-9, desoxyribose nucleic acid, viral haemagglutinin inhibition assay, Mus musculus, Element, Caspase-14 subunit p10, mice, Swiss Mouse, NC70F, INSDC_feature:gene, Caspase-14 subunit p19, Type 2, MICE, Component, Type 1, domesticus, Nc70F, recruitment (subjects), Dependent for Toilet Use, Agents, IMD31B, Neither Case nor Control, IMD31C, Isgf3g, bacterial transcription, IMD31A, Neither, ds DNA, Cells, E(var)62, Mouse, p48, DNA, Antivirals, ISGF3G, Interferon, XML Bound, Contingent, 3.4.22.-, atypia, gaga, transcription, biological signaling, Important, DNS, (Deoxyribonucleotide)n, Conditional, Contingency, Importance, L Isomer, {Cells}, E(var)3-trl, GAGA, mini-ICE, fastening fasteners) with help, disfunctional, IPOA, dependent, Deoxyribonucleic acids, Antiviral Drug, Affected, Agent, Cellularity Measurement, Cellularity, Functional Component, Deoxyribonucleic Acid, Dressing (includes tying shoes, CG9343, House, INSDC_qualifier:promoter, Sites, Mus musculus domesticus, atypical, 2-aminopropanoic acid, Mice, Mediator, Site, Drugs, hemagglutination inhibition, Bathes with Help, DmelCG33261, Swiss, cell, plasmid binding, Target, Double Stranded, Deoxyribonucleic acid, Trl-GAGA, HIA, Alanine, Combining Site, Cellularity Index, microtubule/chromatin interaction, Immune Response, Percent Cellularity, SOD, CELLULAR, Gaga, (Deoxyribonucleotide)m, ALA, Immune Process, Combining Sites, promoter sequence, Including, Cellularity Grade, cellular transcription, structure-specific DNA binding, ALS, Adf-2-519, Dependent, Essential, DNAn+1, TRL, Targeted, L Alanine, function, L-Alanine, defective, Binding Site, Antiviral Drugs, L-Isomer, Conditionality, Cell, Abufène, strain, DD6G4-4, 2-Aminopropionic acid, Protein Functional Component, Mus, ISGF-3, l(3)s2325, anon-EST:fe2E12, affected, trl, Bathing self with help, structure specific DNA binding, ALS1, ds-DNA, L-Isomer Alanine, INSDC_feature:regulatory, (L)-Alanine, Destination, biological activity, 2010005J02Rik, Protein Component, hSod1, DNA-templated, Combining, House Mice, 2-Aminopropanoic acid, Alanin, TfGAGA/Adf-2, Heparin-binding growth factor 9, Dresses with Help, signalling, Laboratory Mice, Drug, ISGF3, Generated, Mediated, signalling process, Bristol Stool Type 2, FGF-9, Bristol Stool Type 1, HEL-S-44, Isolation of Nuclei TAgged in specific Cell Types, Dependent Bathing, Desoxyribonukleinsaeure, Response, Cell Types, Inclusive, Drug Product Component, Laboratory Mouse, Limitextent, 11alpha, Public Sectors, Laboratory, STAT91, TalANAc, Mus domesticus, Adf2, A4, CASP-14, XStat1, Antiviral, Antiviral Agent, House Mouse, germacrene A synthase activity, Public Enterprise, A, Immune Processes, thymus nucleic acid, Immune Responses, CANDF7, Public Domains, SYNS3, Swiss Mice, alanina, alanine, ecotype, PA1, 13E, DNA-dependent, HBGF-9, Immune, signaling process, C16orf53, AA408197, HAI, Double-Stranded DNA, deoxyribonucleic acids, house mouse, DNAn, CG33261, transcription from bacterial-type RNA polymerase promoter, Kunststoff, single organism signaling, homodimer, (+)-germacrene A synthase activity, close to, IRF-9, DNA-dependent transcription, Process, functional failure, aberrant, completeness, mouse, Irf-9, Double-Stranded, GAST, 2-(acetylamino)-2-deoxy-, Fsrg1, Binding, (Deoxyribonucleotide)n+m, shortened, Glia-activating factor, RING3, Adf-2, Public Domain, GAF, Gaf, FSRG1, Mini-ICE, Domains, cultivar, failure, GAS, HBFG-9, desoxyribose nucleic acid, 6-trans-farnesyl-diphosphate diphosphate-lyase (germacrene-A-forming) activity, Domain, viral haemagglutinin inhibition assay, polymer, Mus musculus, Caspase-14 subunit p10, mice, Swiss Mouse, NC70F, INSDC_feature:gene, Caspase-14 subunit p19, gas, 15S)-, MICE, polymers, experimental procedures, domesticus, Nc70F, DMDA, Sector, Agents, IMD31B, IMD31C, Isgf3g, bacterial transcription, IMD31A, (5Z, ds DNA, E(var)62, Mouse, p48, DNA, Antivirals, short, ISGF3G, Interferon, Fsrg-1, macromolecules, NAT, Nat, 3.4.22.-, atypia, gaga, transcription, biological signaling, Sectors, D17H6S113E, alpha-L-Talopyranuronic acid, DNS, experimental, (Deoxyribonucleotide)n, number, L Isomer, E(var)3-trl, 2-trans, alpha-L-N-acetyltalosaminuronic acid, GAGA, mini-ICE, Copyrights, disfunctional, FSH, IPOA, presence, TYPE, Deoxyribonucleic acids, Antiviral Drug, DAGA4, Agent, Deoxyribonucleic Acid, CG9343, House, Sites, Mus musculus domesticus, atypical, MAM, 2-aminopropanoic acid, SCG3, Mice, Enterprises, Site, Drugs, hemagglutination inhibition, methods, DmelCG33261, Swiss, experimental section, ligand, plasmid binding, stubby, Double Stranded, Deoxyribonucleic acid, Ring3, Public Enterprises, Trl-GAGA, HIA, Alanine, Combining Site, microtubule/chromatin interaction, Abstract, Immune Response, SOD, (Deoxyribonucleotide)m, Gaga, ALA, Enterprise, Immune Process, Combining Sites, cellular transcription, structure-specific DNA binding, polymer molecule, ALS, Adf-2-519, 6-trans-farnesyl-diphosphate diphosphate-lyase [(+)-germacrene-A-forming] activity, DNAn+1, TRL, L Alanine, function, L-Alanine, defective, Binding Site, Antiviral Drugs, L-Isomer, (+)-(10R)-germacrene A synthase activity, LGMD2C, Abufène, strain, DD6G4-4, near to, 2-Aminopropionic acid, count in organism, Mus, ISGF-3, l(3)s2325, Public, AW228947, anon-EST:fe2E12, trl, structure specific DNA binding, mKIAA4005, ds-DNA, ALS1, L-Isomer Alanine, Data Base, (L)-Alanine, biological activity, D6S113E, DMDA1, 2010005J02Rik, Rnf3, RNF3, Frg-1, hSod1, DNA-templated, Combining, House Mice, 2-Aminopropanoic acid, Alanin, TfGAGA/Adf-2, Heparin-binding growth factor 9, signalling, Laboratory Mice, Drug, ISGF3, signalling process, Polymer, FGF-9, approaches, HEL-S-44, Isolation of Nuclei TAgged in specific Cell Types, SCARMD2, vicinity of, Desoxyribonukleinsaeure, Response, Public., quantitative, macromolecule, Laboratory Mouse, alpha-L-2-N-acetylamino-2-desoxytaluronic acid, presence or absence in organismsignalling., DD6G4-4, microtubule/chromatin interaction, biological signaling, structure-specific DNA binding, CANDF7, signalling process, Bristol Stool Type 2, IMD31B, Bristol Stool Type 1, ISGF-3, IMD31C, STAT91, 2010005J02Rik, signaling process, IMD31A, AA408197, plasmid binding, structure specific DNA binding, XStat1, Type 2, Interferon, single organism signaling, Type 1falseBegitt2014 - STAT1 cooperative DNA binding - single GAS polymer model
Begitt2014 - STAT1 cooperative DNA binding - single GAS polymer model
The importance of STAT1-cooperative DNA binding in type 1 and type 2 interferon signalling has been studies using experimental and modelling approaches. The authors have developed two ODE models to describe STAT1 binding to short promoter regions of DNA, namely "single GAS polymer model" and "double GAS polymer model" considering binding to single or double GAS sites, respectively. The length of DNA in the single GAS model was three sites and four sites in double GAS model. This model correspond to the "single GAS polymer model".
This model is described in the article:
STAT1-cooperative DNA binding distinguishes type 1 from type 2 interferon signaling.
Begitt A, Droescher M, Meyer T, Schmid CD, Baker M, Antunes F, Owen MR, Naumann R, Decker T, Vinkemeier U
Nat Immunol. 2014 Feb;15(2):168-76.
Abstract:
STAT1 is an indispensable component of a heterotrimer (ISGF3) and a STAT1 homodimer (GAF) that function as transcription regulators in type 1 and type 2 interferon signaling, respectively. To investigate the importance of STAT1-cooperative DNA binding, we generated gene-targeted mice expressing cooperativity-deficient STAT1 with alanine substituted for Phe77. Neither ISGF3 nor GAF bound DNA cooperatively in the STAT1F77A mouse strain, but type 1 and type 2 interferon responses were affected differently. Type 2 interferon-mediated transcription and antibacterial immunity essentially disappeared owing to defective promoter recruitment of GAF. In contrast, STAT1 recruitment to ISGF3 binding sites and type 1 interferon-dependent responses, including antiviral protection, remained intact. We conclude that STAT1 cooperativity is essential for its biological activity and underlies the cellular responses to type 2, but not type 1 interferon.
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2018-12-212014-01-072013-11-13BIOMD000000050024413774MODEL1311130001BIOMD0000000500GO:0060333GO:0005623GO:000563410090P42225