title: PARP-14 combines with tristetraprolin in the selective posttranscriptional control of macrophage tissue factor expression.
abstract: Tissue factor (TF) (CD142) is a 47 kDa transmembrane cell surface glycoprotein that triggers the extrinsic coagulation cascade and links thrombosis with inflammation. Although macrophage TF expression is known to be regulated at the RNA level, very little is known about the mechanisms involved. Poly(adenosine 5'-diphosphate [ADP]-ribose)-polymerase (PARP)-14 belongs to a family of intracellular proteins that generate ADP-ribose posttranslational adducts. Functional screening of PARP-14-deficient macrophages mice revealed that PARP-14 deficiency leads to increased TF expression and functional activity in macrophages after challenge with bacterial lipopolysaccharide. This was related to an increase in TF messenger RNA (mRNA) stability. Ribonucleoprotein complex immunoprecipitation and biotinylated RNA pull-down assays demonstrated that PARP-14 forms a complex with the mRNA-destabilizing protein tristetraprolin (TTP) and a conserved adenylate-uridylate-rich element in the TF mRNA 3' untranslated region. TF mRNA regulation by PARP-14 was selective, as tumor necrosis factor (TNF)α mRNA, which is also regulated by TTP, was not altered in PARP-14 deficient macrophages. Consistent with the in vitro data, TF expression and TF activity, but not TNFα expression, were increased in Parp14(-/-) mice in vivo. Our study provides a novel mechanism for the posttranscriptional regulation of TF expression, indicating that this is selectively regulated by PARP-14.
authors.affiliation: Vascular Sciences Section, National Heart and Lung Institute, Imperial College London, United Kingdom;
authors.forename: M Bilal
authors.initials: MB
authors.lastname: Iqbal
authors.affiliation: Vascular Sciences Section, National Heart and Lung Institute, Imperial College London, United Kingdom;
authors.forename: Michael
authors.initials: M
authors.lastname: Johns
authors.affiliation: Vascular Sciences Section, National Heart and Lung Institute, Imperial College London, United Kingdom;
authors.forename: Jun
authors.initials: J
authors.lastname: Cao
authors.affiliation: Vascular Sciences Section, National Heart and Lung Institute, Imperial College London, United Kingdom;
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Vascular Sciences Section, National Heart and Lung Institute, Imperial College London, United Kingdom;
authors.forename: Sheng-Chun
authors.initials: SC
authors.lastname: Yu
authors.affiliation: Vascular Sciences Section, National Heart and Lung Institute, Imperial College London, United Kingdom;
authors.forename: Gareth D
authors.initials: GD
authors.lastname: Hyde
authors.affiliation: Department of Medicine, Imperial College London, United Kingdom;
authors.forename: Michael A
authors.initials: MA
authors.lastname: Laffan
authors.affiliation: Kennedy Institute of Rheumatology Division, University of Oxford, Oxford, United Kingdom;
authors.forename: Francesco P
authors.initials: FP
authors.lastname: Marchese
authors.affiliation: Department of Pathology, Microbiology & Immunology, Vanderbilt University, Nashville, TN;
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Cho
authors.affiliation: Centre for Translational Inflammation Research, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Clark
authors.affiliation: Department of Medicine, Imperial College London, United Kingdom;
authors.forename: Felicity N
authors.initials: FN
authors.lastname: Gavins
authors.affiliation: Department of Medicine, Imperial College London, United Kingdom;
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Woollard
authors.affiliation: National Institute of Environmental Health Sciences, Research Triangle Park, NC; and.
authors.forename: Perry J
authors.initials: PJ
authors.lastname: Blackshear
authors.affiliation: Department of Medicine, McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Nigel
authors.initials: N
authors.lastname: Mackman
authors.affiliation: Kennedy Institute of Rheumatology Division, University of Oxford, Oxford, United Kingdom;
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Dean
authors.affiliation: Department of Pathology, Microbiology & Immunology, Vanderbilt University, Nashville, TN;
authors.forename: Mark
authors.initials: M
authors.lastname: Boothby
authors.affiliation: Vascular Sciences Section, National Heart and Lung Institute, Imperial College London, United Kingdom;
authors.forename: Dorian O
authors.initials: DO
authors.lastname: Haskard
mesh_terms: D020413:3' Untranslated Regions / Q000502:physiology; D000818:Animals; D005786:Gene Expression Regulation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D020871:RNA Stability / Q000187:drug effects / Q000502:physiology; D013925:Thromboplastin / Q000096:biosynthesis* / Q000235:genetics; D051816:Tristetraprolin / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D008070:Lipopolysaccharides; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; C497553:Zfp36 protein, mouse; D013925:Thromboplastin; C522628:Parp14 protein, mouse; D011065:Poly(ADP-ribose) Polymerases