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

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.

Keywords: ATFS-1; UPRmt; ZIP-3; immunity; mitochondrial UPR.