The <i>Legionella pneumophila</i> effector PieF modulates mRNA stability through association with eukaryotic CCR4−NOT

The intracellular bacterial pathogen <i>Legionella pneumophila</i> targets conserved eukaryotic pathways to establish a replicative niche inside host cells. With a host range that spans billions of years of evolution (from protists to humans), the interaction between <i>L. pneumophila</i> and its hosts frequently involves conserved eukaryotic pathways (protein translation, ubiquitination, membrane trafficking, autophagy, and the cytoskeleton). Here, we present the identification of a new, highly conserved host target of <i>L. pneumophila</i> effectors: the CCR4-NOT complex. CCR4-NOT modulates mRNA stability in eukaryotes from yeast to humans, making it an attractive target for a generalist pathogen, such as <i>L. pneumophila</i>. We show that the uncharacterized <i>L. pneumophila</i> effector PieF specifically targets one component of this complex, the deadenylase subunit CNOT7/8. We show that the interaction between PieF and CNOT7 is direct, occurs with high affinity, and reshapes the catalytic activity, localization, and composition of the complex across evolutionarily diverse eukaryotic cells.