Multivalent interactions with CCR4–NOT and PABPC1 determine mRNA repression efficiency by tristetraprolin
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...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62741-7 |
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| Summary: | 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. |
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| ISSN: | 2041-1723 |