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Updated: Apr 22, 2026
Studying RNA Interactors of Protein Kinase RNA-Activated during the Mammalian Cell Cycle
Published on: March 5, 2019
PARP-14 combines with tristetraprolin in the selective posttranscriptional control of macrophage tissue factor
M Bilal Iqbal1, Michael Johns1, Jun Cao1
1Vascular Sciences Section, National Heart and Lung Institute, Imperial College London, United Kingdom;
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.
Insights
Poly(ADP-ribose)-polymerase (PARP)-14 selectively regulates tissue factor (TF) mRNA stability in macrophages. PARP-14 deficiency increases TF expression and activity by stabilizing TF mRNA, impacting thrombosis and inflammation.
Area of Science:
- Molecular Biology
- Immunology
- Hematology
Background:
- Tissue factor (TF) is a key initiator of the extrinsic coagulation cascade, linking thrombosis and inflammation.
- Macrophage TF expression is regulated post-transcriptionally, but the underlying mechanisms remain largely unknown.
- Poly(ADP-ribose)-polymerase (PARP)-14 is an intracellular protein involved in ADP-ribose posttranslational modifications.
Purpose of the Study:
- To investigate the role of PARP-14 in the posttranscriptional regulation of macrophage TF expression.
- To elucidate the molecular mechanism by which PARP-14 controls TF mRNA stability.
Main Methods:
- Utilized PARP-14-deficient macrophages and mice models.
- Employed ribonucleoprotein complex immunoprecipitation and biotinylated RNA pull-down assays.
- Analyzed TF and tumor necrosis factor-alpha (TNFα) mRNA stability and expression levels.
Main Results:
- PARP-14 deficiency in macrophages resulted in increased TF expression and activity following lipopolysaccharide challenge.
- This increase was attributed to enhanced TF mRNA stability, mediated by PARP-14's interaction with tristetraprolin (TTP) and the TF mRNA 3' UTR.
- TF mRNA regulation by PARP-14 was selective, as TNFα mRNA stability and expression remained unaffected.
Conclusions:
- PARP-14 plays a crucial role in the selective posttranscriptional regulation of TF expression in macrophages.
- PARP-14 stabilizes TF mRNA by interacting with TTP, providing a novel regulatory mechanism.
- This finding offers new insights into the control of coagulation and inflammation at the posttranscriptional level.
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