Mitochondrial UPR repression during Pseudomonas aeruginosa infection requires the bZIP protein ZIP-3

Abstract

Significance Mitochondria are the compartments in animal cells that produce the most energy and are often targets of bacterial toxins during infection. In response, hosts employ an adaptive transcriptional response known as the mitochondrial unfolded protein response (UPRmt) to maintain mitochondrial function and eliminate the toxic bacteria. Here, we demonstrate that the pathogen Pseudomonas aeruginosa exploits a negative regulatory mechanism built into the UPRmt to prevent activation of the antibacterial response. Impressively, if the negative regulator ZIP-3 is inhibited, worms are resistant to infection as they are able to effectively activate the UPRmt. The pathogen potentially evolved means to impair the UPRmt because a virulence determinant that ordinarily maintains biofilm metabolism perturbs mitochondrial function eliciting the antibacterial response. 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 (UPRmt) to detect and respond to mitochondrial dysfunction as an indicator of infection. The UPRmt 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 UPRmt activation. Here, we demonstrate that Pseudomonas aeruginosa exploits an intrinsic negative regulatory mechanism mediated by the Caenorhabditis elegans bZIP protein ZIP-3 to repress UPRmt activation. Strikingly, worms lacking zip-3 were impervious to Pseudomonas aeruginosa-mediated UPRmt repression and resistant to infection. Pathogen-secreted phenazines perturbed mitochondrial function and were the primary cause of UPRmt activation, consistent with these molecules being electron shuttles and virulence determinants. Surprisingly, Pseudomonas aeruginosa unable to produce phenazines and thus elicit UPRmt activation were hypertoxic in zip-3–deletion worms. These data emphasize the significance of virulence-mediated UPRmt repression and the potency of the UPRmt as an antibacterial response.