Dynamic proteomics profiling ofLegionella pneumophilainfection unveils modulation of the host mitochondrial stress response pathway

Abstract

SUMMARYThe human pathogenLegionella pneumophila (L.p.)secretes ~330 bacterial effector proteins into the host cell which interfere with numerous cellular pathways and often regulate host cell proteins through post-translational modifications. However, the cellular targets and functions of mostL.p.effectors are not known. In order to obtain a global overview of potential targets of these effectors, we analyzed the host cell proteome, ubiquitinome, and phosphoproteome duringL.p.infection. Our analysis reveals dramatic spatiotemporal changes in the host cell proteome that are dependent on the secretion of bacterial effectors. Strikingly, we show thatL.p.substantially reshapes the mitochondrial proteome and modulates mitochondrial stress response pathways such as the mitochondrial unfolded protein response (UPRmt). To our knowledge, this is the first evidence of manipulation of the UPRmtby a bacterial pathogen in mammalian cells. In addition, we have identified a previously uncharacterizedL.p.effector that is targeted to host cell mitochondria and protects mitochondrial network integrity during mitochondrial stress.