Multivalent interactions with CCR4–NOT and PABPC1 determine mRNA repression efficiency by tristetraprolin

Filip Pekovic, Wi S. Lai, Joshua Corbo, Stephanie N. Hicks, Keiko Luke, Perry J. Blackshear () and Eugene Valkov ()
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Filip Pekovic: National Institutes of Health
Wi S. Lai: Research Triangle Park
Joshua Corbo: National Institutes of Health
Stephanie N. Hicks: Research Triangle Park
Keiko Luke: National Institutes of Health
Perry J. Blackshear: Research Triangle Park
Eugene Valkov: National Institutes of Health

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Tristetraprolin family of proteins regulate mRNA stability by binding to specific AU-rich elements in transcripts. This binding promotes the shortening of the mRNA poly(A) tail, or deadenylation, initiating mRNA degradation. The CCR4–NOT complex plays a central role in deadenylation, while the cytoplasmic poly(A)-binding protein PABPC1 typically protects mRNAs from decay. Here, we investigate how tristetraprolin interacts with CCR4–NOT and PABPC1 to control mRNA stability. Using purified proteins and in vitro assays, we find that tristetraprolin engages CCR4–NOT through multiple interaction sites and promotes its activity, emphasizing the importance of multivalent binding for efficient deadenylation. Phosphorylation of tristetraprolin does not affect its interaction with CCR4–NOT or its deadenylation activity, but is essential for tristetraprolin’s binding to PABPC1. We propose that tristetraprolin promotes the processive deadenylation activity of CCR4–NOT on mRNAs containing AU-rich elements, with phosphorylation-dependent interactions with PABPC1 potentially enhancing deadenylation and promoting regulated mRNA decay.

Date: 2025
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DOI: 10.1038/s41467-025-62741-7

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