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The Legionella pneumophila effector PieF modulates mRNA stability through association with eukaryotic CCR4-NOT
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DOI：10.1128/msphere.00891-24.png)
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Abstract
En 中文
The eukaryotic CCR4-NOT deadenylase complex is a highly conserved regulator of mRNA metabolism that influences the expression of the complete transcriptome, representing a prime target for a generalist bacterial pathogen. We show that a translocated bacterial effector protein, PieF (Lpg1972) of Legionella pneumophila, directly interacts with the CNOT7/8 nuclease module of CCR4-NOT, with a dissociation constant in the low nanomolar range. PieF is a robust in vitro inhibitor of the DEDD-type nuclease, CNOT7, acting in a stoichiometric, dose-dependent manner. Heterologous expression of PieF phenocopies knockout of the CNOT7 ortholog (POP2) in Saccharomyces cerevisiae, resulting in 6-azauracil sensitivity. In mammalian cells, expression of PieF leads to a variety of quantifiable phenotypes: PieF silences gene expression and reduces mRNA steady-state levels when artificially tethered to a reporter transcript, and its overexpression results in the nuclear exclusion of CNOT7. PieF expression also disrupts the association between CNOT6/6L EEP-type nucleases and CNOT7. Adding to the complexities of PieF activity in vivo, we identified a separate domain of PieF responsible for binding to eukaryotic kinases. Unlike what we observe for CNOT6/6L, we show that these interactions can occur concomitantly with PieF's binding to CNOT7. Collectively, this work reveals a new, highly conserved target of L. pneumophila effectors and suggests a mechanism by which the pathogen may be modulating host mRNA stability and expression during infection.
Keywords:
Legionella pneumophila
host-pathogen interaction
deadenylation
CCR4-NOT
mRNA stability
PieF
effectors
CNOT7 inhibition
CNOT7/8
Caf1
Pop2
DEDD
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