Intracellular pathogen effector reprograms host gene expression by inhibiting mRNA decay
Yevgen Levdansky,
Justin C. Deme,
David J. Turner,
Claire T. Piczak,
Filip Pekovic,
Anna L. Valkov,
Sergey G. Tarasov,
Susan M. Lea () and
Eugene Valkov ()
Additional contact information
Yevgen Levdansky: National Institutes of Health
Justin C. Deme: National Institutes of Health
David J. Turner: National Institutes of Health
Claire T. Piczak: National Institutes of Health
Filip Pekovic: National Institutes of Health
Anna L. Valkov: National Institutes of Health
Sergey G. Tarasov: National Institutes of Health
Susan M. Lea: National Institutes of Health
Eugene Valkov: National Institutes of Health
Nature Communications, 2025, vol. 16, issue 1, 1-11
Abstract:
Abstract Legionella pneumophila, an intracellular bacterial pathogen, injects effector proteins into host cells to manipulate cellular processes and promote its survival and proliferation. Here, we reveal a unique mechanism by which the Legionella effector PieF perturbs host mRNA decay by targeting the human CCR4–NOT deadenylase complex. High-resolution cryo-electron microscopy structures and biochemical analyses reveal that PieF binds with nanomolar affinity to the NOT7 and NOT8 catalytic subunits of CCR4–NOT, obstructing RNA access and displacing a catalytic Mg²⁺ ion from the active site. Additionally, PieF prevents NOT7/8 from associating with their partner deadenylases NOT6/6L, inhibiting the assembly of a functional deadenylase complex. Consequently, PieF robustly blocks mRNA poly(A) tail shortening and degradation with striking potency and selectivity for NOT7/8. This inhibition of deadenylation by PieF impedes cell cycle progression in human cells, revealing a novel bacterial strategy to modulate host gene expression.
Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61194-2
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DOI: 10.1038/s41467-025-61194-2
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