A link between an intracellular stress response, bacterial infection and triggering of the innate immune response is shown in Caenorhabditis elegans; exposure to the pathogen Pseudomonas aeruginosa caused activation of the transcription factor ATFS-1 and innate immunity that is regulated by the mitochondrial unfolded protein response. The mitochondrial unfolded protein response (UPRmt) is a stress response that activates transcription of nuclear-encoded mitochondrial chaperone genes to promote protein homeostasis within the mitochondrion. Here Mark Pellegrino et al. provide evidence that mitochondrial dysfunction, and activation of the UPRmt, leads to upregulation of innate immunity and promotes pathogen resistance in Caenorhabditis elegans exposed to Pseudomonas aeruginosa. Metazoans identify and eliminate bacterial pathogens in microbe-rich environments such as the intestinal lumen; however, the mechanisms are unclear. Host cells could potentially use intracellular surveillance or stress response programs to detect pathogens that target monitored cellular activities and then initiate innate immune responses1,2,3. Mitochondrial function is evaluated by monitoring mitochondrial protein import efficiency of the transcription factor ATFS-1, which mediates the mitochondrial unfolded protein response (UPRmt). During mitochondrial stress, mitochondrial import is impaired4, allowing ATFS-1 to traffic to the nucleus where it mediates a transcriptional response to re-establish mitochondrial homeostasis5. Here we examined the role of ATFS-1 in Caenorhabditis elegans during pathogen exposure, because during mitochondrial stress ATFS-1 induced not only mitochondrial protective genes but also innate immune genes that included a secreted lysozyme and anti-microbial peptides. Exposure to the pathogen Pseudomonas aeruginosa caused mitochondrial dysfunction and activation of the UPRmt. C. elegans lacking atfs-1 were susceptible to P. aeruginosa, whereas hyper-activation of ATFS-1 and the UPRmt improved clearance of P. aeruginosa from the intestine and prolonged C. elegans survival in a manner mainly independent of known innate immune pathways6,7. We propose that ATFS-1 import efficiency and the UPRmt is a means to detect pathogens that target mitochondria and initiate a protective innate immune response.

Significance: Pathogens express virulence factors to support their growth and reproduction while hosts activate various immune processes to promote pathogen clearance and minimize damage. In this study, we establish a new role for pyoverdin, an iron-binding siderophore produced by the bacterium Pseudomonas aeruginosa . In addition to promoting growth by acquiring iron, pyoverdin serves as a secreted bacterial toxin that disrupts mitochondria and iron homeostasis in Caenorhabditis elegans . We show that exposure to pyoverdin triggers mitochondrial damage and subsequent mitophagy (lysosomal degradation of damaged mitochondria). Importantly, mitophagy confers a protective effect against exposure to either pyoverdin or to a synthetic iron chelator, demonstrating a function for mitophagy in innate immunity. Finally, we show that iron chelation causes mitophagy in mammalian cells.

Organisms are constantly challenged by stresses and privations and require adaptive responses for their survival. The forkhead box O (FOXO) transcription factor DAF-16 (hereafter referred to as DAF-16/FOXO) is a central nexus in these responses, but despite its importance little is known about how it regulates its target genes. Proteomic identification of DAF-16/FOXO-binding partners in Caenorhabditis elegans and their subsequent functional evaluation by RNA interference revealed several candidate DAF-16/FOXO cofactors, most notably the chromatin remodeller SWI/SNF. DAF-16/FOXO and SWI/SNF form a complex and globally co-localize at DAF-16/FOXO target promoters. We show that specifically for gene activation, DAF-16/FOXO depends on SWI/SNF, facilitating SWI/SNF recruitment to target promoters, to activate transcription by presumed remodelling of local chromatin. For the animal, this translates into an essential role for SWI/SNF in DAF-16/FOXO-mediated processes, in particular dauer formation, stress resistance and the promotion of longevity. Thus, we give insight into the mechanisms of DAF-16/FOXO-mediated transcriptional regulation and establish a critical link between ATP-dependent chromatin remodelling and lifespan regulation.