| Abstract: |
Mitochondria generate most cellular energy and are targeted by multiple pathogens during infection. In turn, metazoans employ surveillance mechanisms such as the mitochondrial unfolded protein response (UPR mt ) to detect and respond to mitochondrial dysfunction as an indicator of infection. The UPR mt is an adaptive transcriptional program regulated by the transcription factor ATFS-1, which induces genes that promote mitochondrial recovery and innate immunity. The bacterial pathogen Pseudomonas aeruginosa produces toxins that disrupt oxidative phosphorylation (OXPHOS), resulting in UPR mt activation. Here, we demonstrate that Pseudomonas aeruginosa exploits an intrinsic negative regulatory mechanism mediated by the Caenorhabditis elegans bZIP protein ZIP-3 to repress UPR mt activation. Strikingly, worms lacking zip-3 were impervious to Pseudomonas aeruginosa-mediated UPR mt repression and resistant to infection. Pathogen-secreted phenazines perturbed mitochondrial function and were the primary cause of UPR mt activation, consistent with these molecules being electron shuttles and virulence determinants. Surprisingly, Pseudomonas aeruginosa unable to produce phenazines and thus elicit UPR mt activation were hypertoxic in zip-3-deletion worms. These data emphasize the significance of virulence-mediated UPR mt repression and the potency of the UPR mt as an antibacterial response. © 2019 National Academy of Sciences. All Rights Reserved. |
