PARP-14 combines with tristetraprolin in the selective posttranscriptional control of macrophage tissue factor expression

M. Bilal Iqbal, Michael Johns, Jun Cao, Yu Liu, Sheng Chun Yu, Gareth D. Hyde, Michael A. Laffan, Francesco P. Marchese, Sung Hoon Cho, Andrew R. Clark, Felicity N. Gavins, Kevin J. Woollard, Perry J. Blackshear, Nigel Mackman, Jonathan L. Dean, Mark Boothby, Dorian O. Haskard*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

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-deficientmacrophagesmice 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.

Original languageEnglish
Pages (from-to)3646-3655
Number of pages10
JournalBlood
Volume124
Issue number24
Early online date7 Oct 2014
DOIs
Publication statusPublished - 4 Dec 2014

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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