Legionella Metaeffector Exploits Host Proteasome to Temporally Regulate Cognate Effector

Abstract

Pathogen-associated secretion systems translocate numerous effector proteins into eukaryotic host cells to coordinate cellular processes important for infection. Spatiotemporal regulation is therefore important for modulating distinct activities of effectors at different stages of infection. Here we provide the first evidence of “metaeffector,” a designation for an effector protein that regulates the function of another effector within the host cell. Legionella LubX protein functions as an E3 ubiquitin ligase that hijacks the host proteasome to specifically target the bacterial effector protein SidH for degradation. Delayed delivery of LubX to the host cytoplasm leads to the shutdown of SidH within the host cells at later stages of infection. This demonstrates a sophisticated level of coevolution between eukaryotic cells and L. pneumophila involving an effector that functions as a key regulator to temporally coordinate the function of a cognate effector protein.

Author Summary

Many bacterial pathogens encode a large array of “effector proteins” that are essential for successful infection. By definition, effector proteins are synthesized in bacteria and transported from bacteria into host cells. Within host cells, effector proteins directly interact with host factors in order to modulate their functions. Effector expression, translocation or activity within host cells must be precisely regulated over infection stages. Here we demonstrate the first example of an effector protein which targets and regulates another effector within host cells: Legionella effector protein LubX targets another effector protein SidH to proteasome-mediated protein degradation in the host cells. Expression and delivery of these effector proteins are differentially regulated, which results in LubX-dependent SidH shutdown at late stages of infection. We propose the designation “metaeffector” for this class of bacterial effector protein: an effector that targets and regulates another effector within host cells. Future studies may reveal that metaeffectors which play critical roles in coordinating the functional expression of other effectors spatiotemporally are prevalent among bacterial pathogens.