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Updated: Sep 11, 2025

Exploring Sequence Space to Identify Binding Sites for Regulatory RNA-Binding Proteins
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Multivalent interactions with CCR4-NOT and PABPC1 determine mRNA repression efficiency by tristetraprolin

Filip Pekovic1, Wi S Lai2, Joshua Corbo1

  • 1National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA.

Nature Communications
|August 13, 2025
PubMed

Insights

Tristetraprolin proteins control mRNA decay by interacting with the CCR4-NOT complex and PABPC1. Phosphorylation regulates these interactions, influencing mRNA stability and degradation.

Area of Science:

  • Molecular Biology
  • Gene Regulation
  • Protein-RNA Interactions

Background:

  • Tristetraprolin proteins bind AU-rich elements in mRNA to regulate stability.
  • mRNA deadenylation, a key step in degradation, is mediated by the CCR4-NOT complex.
  • Cytoplasmic poly(A)-binding protein PABPC1 typically protects mRNA from decay.

Purpose of the Study:

  • To investigate the interaction mechanisms between tristetraprolin, CCR4-NOT, and PABPC1.
  • To elucidate how these interactions control mRNA stability and degradation.
  • To understand the role of tristetraprolin phosphorylation in these processes.

Main Methods:

  • In vitro biochemical assays using purified proteins.
  • Analysis of protein-protein interactions.
  • Assessment of mRNA deadenylation and degradation rates.

Main Results:

  • Tristetraprolin binds CCR4-NOT through multiple sites, enhancing its deadenylation activity.
  • Tristetraprolin phosphorylation is not required for CCR4-NOT interaction or deadenylation.
  • Phosphorylation is essential for tristetraprolin binding to PABPC1.

Conclusions:

  • Tristetraprolin promotes processive deadenylation by CCR4-NOT on specific mRNAs.
  • Phosphorylation-dependent PABPC1 interaction may further enhance deadenylation and regulated mRNA decay.
  • This study reveals a complex regulatory mechanism for mRNA stability involving tristetraprolin family proteins.

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